Sara Mozelle Centuori

Interests

No activities entered.

Courses

No activities entered.

Scholarly Contributions

Journals/Publications

• Clements, A. N., Casillas, A. L., Flores, C. E., Liou, H., Toth, R. K., Chauhan, S. S., Sutterby, K., Deshmukh, S. K., Wu, S., Xiu, J., Farrell, A., Radovich, M., Nabhan, C., Heath, E. I., McKay, R. R., Subah, N., Centuori, S., Wheeler, T. J., Cress, A. E., , Rogers, G. C., et al. (2024). Inhibition of PIM kinase in tumor associated macrophages suppresses inflammasome activation and sensitizes prostate cancer to immunotherapy. bioRxiv : the preprint server for biology.
  More info

  Immunotherapy has changed the treatment paradigm for many types of cancer, but immune checkpoint inhibitors (ICIs) have not shown benefit in prostate cancer (PCa). Chronic inflammation contributes to the immunosuppressive prostate tumor microenvironment (TME) and is associated with poor response to ICIs. The primary source of inflammatory cytokine production is the inflammasome. Here, we identify PIM kinases as important regulators of inflammasome activation in tumor associated macrophages (TAMs). Analysis of clinical data from a cohort of treatment naïve, hormone responsive PCa patients revealed that tumors from patients with high PIM1/2/3 display an immunosuppressive TME characterized by high inflammation (IL-1β and TNFα) and a high density of repressive immune cells, most notably TAMs. Strikingly, macrophage-specific knockout of PIM reduced tumor growth in syngeneic models of prostate cancer. Transcriptional analyses indicate that eliminating PIM from macrophages enhanced the adaptive immune response and increased cytotoxic immune cells. Combined treatment with PIM inhibitors and ICIs synergistically reduced tumor growth. Immune profiling revealed that PIM inhibitors sensitized PCa tumors to ICIs by increasing tumor suppressive TAMs and increasing the activation of cytotoxic T cells. Collectively, our data implicate macrophage PIM as a driver of inflammation that limits the potency of ICIs and provides preclinical evidence that PIM inhibitors are an effective strategy to improve the efficacy of immunotherapy in prostate cancer.
• Bauman, J. E., Saba, N. F., Roe, D., Bauman, J. R., Kaczmar, J., Bhatia, A., Muzaffar, J., Julian, R., Wang, S., Bearelly, S., Baker, A., Steuer, C., Giri, A., Burtness, B., Centuori, S., Caulin, C., Klein, R., Saboda, K., Obara, S., & Chung, C. H. (2023). Randomized Phase II Trial of Ficlatuzumab With or Without Cetuximab in Pan-Refractory, Recurrent/Metastatic Head and Neck Cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 41(22), 3851-3862.
  More info

  Primary or acquired resistance to cetuximab, an antiepidermal growth factor receptor monoclonal antibody (mAb), minimizes its utility in recurrent/metastatic head and neck squamous cell carcinoma (HNSCC). Aberrant hepatocyte growth factor/cMet pathway activation is an established resistance mechanism. Dual pathway targeting may overcome resistance.
• Centuori, S., Chalasani, P., Chow, H. S., Guillen-Rodriguez, J., Pinto, L. E., Roe, D. J., & Tapia, E. (2023). Abstract P065: Effects of metformin on breast tissue inflammation in premenopausal women with components of metabolic syndrome. Cancer Prevention Research, 16(1_Supplement), P065-P065. doi:10.1158/1940-6215.precprev22-p065
• Parsons, J., Pinto, P., Pavlovich, C., Uchio, E., Nguyen, M., Kim, H., Gulley, J., Sater, H., Jamieson, C., Hsu, C., Wojtowicz, M., House, M., Schlom, J., Donahue, R., Dahut, W., Madan, R., Bailey, S., Centuori, S., Bauman, J., , Parnes, H., et al. (2023). A Phase 2, Double-blind, Randomized Controlled Trial of PROSTVAC in Prostate Cancer Patients on Active Surveillance. European Urology Focus, 9(3). doi:10.1016/j.euf.2022.12.002
  More info

  Background: There is an unmet clinical need for interventions to prevent disease progression in patients with localized prostate cancer on active surveillance (AS). Objective: To determine the immunologic response to the PROSTVAC vaccine and the clinical indicators of disease progression in patients with localized prostate cancer on AS. Design, setting, and participants: This was a phase 2, double-blind, randomized controlled trial in 154 men with low- or intermediate-risk prostate cancer on AS. Intervention: Participants were randomized (2:1) to receive seven doses of subcutaneous PROSTVAC, a vaccinia/fowlpox viral vector–based immunotherapy containing a prostate-specific antigen (PSA) transgene and three T-cell co-stimulatory molecules, or an empty fowlpox vector (EV) over 140 d. Outcome measurements and statistical analysis: The primary outcome was the change from baseline in CD4 and CD8 T-cell infiltration in biopsy tumor tissue. Key secondary outcomes were safety and changes in prostate biopsy tumor pathology, peripheral antigen-specific T cells, and serum PSA. Continuous variables were compared using nonparametric tests. Categorical variables were compared using Fisher's exact test. Results and limitations: The PROSTVAC/EV vaccination was well tolerated. All except one participant completed the vaccination series. Changes in CD4 or CD8 density in biopsy tumor tissue did not differ between the PROSTVAC and EV arms. The proportions of patients with Gleason upgrading to grade group 3 after treatment was similar between the arms. There were no differences in postvaccination peripheral T-cell responses or the PSA change from baseline to 6-mo post-treatment follow-up between the groups. Conclusions: In this first-of-kind trial of immunotherapy in patients on AS for prostate cancer, PROSTVAC did not elicit more favorable prostate tissue or peripheral T-cell responses than the EV. There was no difference between the arms in clinicopathologic effects. Despite the null findings, this is the first study reporting the feasibility and acceptability of an immunotherapy intervention in the AS setting. Patient summary: We looked at responses after an experimental prostate cancer vaccine in patients with prostate cancer on active surveillance (AS). Participants who received the vaccine did not show more favorable outcomes than those receiving the control. Despite these findings, this is the first report showing the feasibility and acceptability of immunotherapy for prostate cancer in patients on AS.
• Bailey, S., Bauman, J. E., Centuori, S., Chow, H. H., Donahue, R. N., Gulley, J. L., Hsu, C., Jamieson, C., Kim, H. L., Nguyen, M. M., Parnes, H. L., Parsons, J. K., Pavlovich, C. P., Pinto, P. A., Sater, H. A., Schlom, J., Uchio, E. M., & Wojtowicz, M. E. (2022). Immunotherapy to prevent progression on active surveillance study (IPASS): A phase II, randomized, double-blind, controlled trial of PROSTVAC in prostate cancer patients who are candidates for active surveillance.. Journal of Clinical Oncology, 40(6_suppl), 249-249. doi:10.1200/jco.2022.40.6_suppl.249
  More info

  249 Background: Immunotherapy could potentially prevent disease progression for early-stage prostate cancer. In this randomized Phase 2 clinical trial, we evaluated the clinical effects of PROSTVAC, a vaccinia/fowlpox viral vector-based immunotherapy that contains PSA and three T-cell costimulatory molecules, in patients with localized prostate cancer. Methods:154 patients with clinically localized, low- or favorable intermediate-risk prostate cancer active surveillance were randomized (2:1) to receive 7 doses of subcutaneous PROSTVAC or placebo (empty fowlpox vector) over 140 days. Post-intervention prostate biopsy was performed 7-14 days after the last dose. Participants were followed for 6 months post-treatment. The primary outcome was change from baseline to post-vaccination in CD4 and CD8 T cell infiltration in biopsy tumor tissue. Secondary outcomes included changes in prostate biopsy Gleason grade (Grade Group) and serum PSA. Results: There were no differences in CD4 and CD8 densities (count of cells/mm2) in post-treatment biopsy tumor tissue between groups ( p = 0.63 and p = 0.75, respectively). Compared to placebo, patients who received PROSTVAC were less likely to demonstrate upgrading at follow-up biopsy, but this difference did not attain significance (22% vs. 40%, p= 0.08). There was no difference in the change of PSA from baseline to 6 months post-treatment between arms ( p= 0.30). Conclusions: In this first-of-kind trial of immunotherapy for localized prostate cancer, PROSTVAC was well tolerated but did not elicit significant prostate tissue T-cell responses compared to placebo. The favorable post-treatment biopsy grade findings in PROSTVAC patients merit further evaluation and longer-term clinical follow-up. Clinical trial information: NCT02326805.
• Bauman, J. E., Hsu, C. H., Centuori, S., Guillen-Rodriguez, J., Garland, L. L., Ho, E., Padi, M., Bageerathan, V., Bengtson, L., Wojtowicz, M., Szabo, E., & Chow, H. S. (2022). Randomized Crossover Trial Evaluating Detoxification of Tobacco Carcinogens by Broccoli Seed and Sprout Extract in Current Smokers. Cancers, 14(9).
  More info

  Consumption of cruciferous vegetables, rich in the isothiocyanate glucoraphanin, is associated with reduced risk of tobacco-related cancers. Sulforaphane, released by hydrolysis of glucoraphanin, potently induces cytoprotective phase II enzymes. Sulforaphane decreased the incidence of oral cancer in the 4NQO carcinogenesis model. In residents of Qidong, China, broccoli seed and sprout extracts (BSSE) increased detoxification of air pollutants benzene and acrolein, also found in tobacco smoke. This randomized, crossover trial evaluated detoxification of tobacco carcinogens by the BSSE Avmacol in otherwise healthy smokers. Participants were treated for 2 weeks with both low and higher-dose BSSE (148 µmol vs. 296 µmol of glucoraphanin daily), separated by a 2-week washout, with randomization to low-high vs. high-low sequence. The primary endpoint was detoxification of benzene, measured by urinary excretion of its mercapturic acid, SPMA. Secondary endpoints included bioavailability, detoxification of acrolein and crotonaldehyde, modulation by genotype, and toxicity. Forty-nine participants enrolled, including 26 (53%) females with median use of 20 cigarettes/day. Low and higher-dose BSSE showed a mean bioavailability of 11% and 10%, respectively. Higher-dose BSSE significantly upregulated urinary excretion of the mercapturic acids of benzene ( = 0.04), acrolein ( < 0.01), and crotonaldehyde ( = 0.02), independent of genotype. Retention and compliance were high resulting in early study completion. In conclusion, BSSE significantly upregulated detoxification of the tobacco carcinogens benzene, acrolein, and crotonaldehyde in current tobacco smokers.
• Centuori, S. M., & Bauman, J. E. (2022). c-Met Signaling as a Therapeutic Target in Head and Neck Cancer. Cancer journal (Sudbury, Mass.), 28(5), 346-353.
  More info

  Despite a dearth of activating driver mutations in head and neck squamous cell carcinoma (HNSCC), aberrant activation of the oncogenes, epidermal growth factor receptor (EGFR), and c-Met is near-universal in human papillomavirus (HPV)-negative disease. Although EGFR activation drove the successful development of the anti-EGFR monoclonal antibody cetuximab in HNSCC, no c-Met-targeting therapy has gained regulatory approval. Inhibition of the c-Met pathway may subvert oncogenesis within the tumor-intrinsic compartment, blocking tumoral proliferation, invasion, migration, and metastasis, or the tumor-extrinsic compartment, modulating the immunosuppressive tumor microenvironment. This review discusses the rationale and current drug development strategies for targeting c-Met or its exclusive ligand hepatocyte growth factor (HGF) in HNSCC.
• Centuori, S. M., & Bhattacharya, D. (2022). Locally produced autoantibodies in cancer. Cell, 185(7), 1110-1111.
  More info

  The function and antigen-specificities of tumor-infiltrating B cells are mostly unknown. In a new study by Mazor et al., matrix metalloproteinase 14 (MMP14), a self-antigen that is overexpressed by ovarian cancers, is shown to drive B cell activation and autoantibody production in tertiary lymphoid structures (Mazor et al., 2022).
• Centuori, S., Chalasani, P., Chow, S., Cordova, C., Guillen, J., Pinto, L., Roe, D. J., Tapia, E., & Villa-Guilen, D. (2022). Abstract P1-10-02: Effect of metformin on metabolic markers associated with breast cancer risk in a phase II clinical trial in overweight/obese premenopausal women. Cancer Research, 82(4_Supplement), P1-10-02-P1-10-02. doi:10.1158/1538-7445.sabcs21-p1-10-02
• Parsons, J. K., Pinto, P. A., Pavlovich, C. P., Uchio, E., Nguyen, M. N., Kim, H. L., Gulley, J. L., Sater, H. A., Jamieson, C., Hsu, C. H., Wojtowicz, M., House, M., Schlom, J., Donahue, R. N., Dahut, W. L., Madan, R. A., Bailey, S., Centuori, S., Bauman, J. E., , Parnes, H. L., et al. (2022). A Phase 2, Double-blind, Randomized Controlled Trial of PROSTVAC in Prostate Cancer Patients on Active Surveillance. European urology focus.
  More info

  There is an unmet clinical need for interventions to prevent disease progression in patients with localized prostate cancer on active surveillance (AS).
• Baker, A., Bauman, J. E., Bauman, J. R., Bearelly, S., Bhatia, A. K., Burtness, B., Caulin, C., Centuori, S., Chung, C. H., Giri, A., Julian, R. A., Kaczmar, J. M., Muzaffar, J., Obara, S., Roe, D., Saba, N. F., Saboda, K., Steuer, C. E., & Wang, S. (2023). Randomized phase II trial of ficlatuzumab with or without cetuximab in pan-refractory, advanced head and neck squamous cell carcinoma (HNSCC).. Journal of Clinical Oncology, 39(15_suppl), 6015-6015. doi:10.1200/jco.2021.39.15_suppl.6015
• Bauman, J. E., Bengtson, L., Centuori, S., Chow, H. S., Garland, L., Guillen-rodriguez, J., Ho, E., Hsu, C., Szabo, E., & Wojtowicz, M. (2021). Abstract LB221: Randomized crossover trial evaluating detoxication of tobacco carcinogens by broccoli seed and sprout extract in heavy smokers. Cancer Research, 81(13_Supplement), LB221-LB221. doi:10.1158/1538-7445.am2021-lb221
  More info

  Abstract Randomized crossover trial evaluating detoxication of tobacco carcinogens by broccoli seed and sprout extract in heavy smokersJulie E. Bauman, Chiu-Hsieh Hsu, Sara Centuori, Jose Guillen-Rodriguez, Linda Garland, Emily Ho, Lisa Bengtson, Malgorzata Wojtowicz, Eva Szabo, H-H Sherry ChowIntroduction: Diets high in cruciferous vegetables are associated with reduced risk of tobacco-related cancers. Crucifers are rich in the phytochemical glucoraphanin (GR), which is hydrolyzed by myrosinase to its bioactive form, sulforaphane (SF). SF upregulates the NRF2 transcription factor and downstream target genes in the antioxidant response element. As GR is concentrated in broccoli seeds relative to mature plants, broccoli seed preparations (BSP) are under development as chemopreventive agents. BSP increased detoxication of air pollutants including benzene in Qidong, China. Methods: We conducted a randomized crossover trial evaluating the detoxication of benzene and other tobacco carcinogens by the BSP Avmacol, tablets comprised of broccoli seed powder and broccoli sprout extract, in otherwise healthy smokers (≥ 20 pack-years). Each subject was treated with low and high dose BSP (70 vs. 140 GR equivalents daily for 2 weeks), separated by a 2-week washout, with randomization to low-high vs. high-low sequence. The primary endpoint was detoxication of benzene, measured by change in urinary excretion of its mercapturic acid metabolite (S-phenyl mercapturic acid, SPMA). Secondary endpoints included detoxication of the carcinogens acrolein and crotonaldehyde, and SF bioavailability assessed by urinary SF metabolites.Results: 49 subjects were randomized from Feb 2018-Nov 2019: 26 female, mean age 56.3. Treatment-related adverse events (AE) were gastrointestinal; most common were grade 1-2 bloating/cramping/abdominal pain (11; 22%), grade 1 diarrhea (11; 22%), grade 1 flatulence (10; 20%). No grade ≥ 3 AE were observed. One subject withdrew after unrelated AE. Compliance with BSP and biomarker measurements was 98%. Primary and secondary endpoints are presented in the Table. Conclusion: The BSP Avmacol was bioavailable as SF metabolites and significantly increased the acute detoxication products of benzene and acrolein in heavy smokers. Dose LevelChange in Metabolite (IQR)a; N=48P-ValueΔ SF MetabolitesbLow Dose19.93 (6.50, 49.00) nmol/mg Cr
• Centuori, S. M., Caulin, C., & Bauman, J. E. (2021). Precision and Immunoprevention Strategies for Tobacco-Related Head and Neck Cancer Chemoprevention. Current treatment options in oncology, 22(6), 52.
  More info

  To date, there is no FDA-approved chemoprevention approach for tobacco-related HNSCC. Effective chemoprevention approaches validated in sufficiently powered randomized trials are needed to reduce the incidence and improve survival. In this review, we recap the challenges encountered in past chemoprevention trials and discuss emerging approaches, with major focus on green chemoprevention, precision prevention, and immunoprevention. As our current depth of knowledge expands in the arena of cancer immunotherapy, the field of immunoprevention is primed for new discoveries and successes in cancer prevention.
• Dickinson, S. E., Khawam, M., Kirschnerova, V., Vaishampayan, P., Centuori, S. M., Saboda, K., Calvert, V. S., Petricoin, E. F., & Curiel-Lewandrowski, C. (2021). Increased PD-L1 Expression in Human Skin Acutely and Chronically Exposed to UV Irradiation. Photochemistry and photobiology, 97(4), 778-784.
  More info

  Overexpression of PD-L1 (CD274) on tumor cells may represent a hallmark of immune evasion, and overexpression has been documented in several tumors including cutaneous squamous cell carcinoma (cSCC). While PD-L1/PD-1 activity in the skin has been primarily described in inflammatory models, our goal was to examine PD-L1 expression in human keratinocytes exposed to UV irradiation. We assessed PD-L1 expression in human sun-protected (SP) and sun-damaged (SD) skin, actinic keratosis (AK), and cSCC using IHC and protein microarray. Both methods found low baseline levels of PD-L1 in SP and SD skin and significantly increased expression in cSCC. Next, we examined PD-L1 expression in acute models of UV exposure. In human SP skin exposed to 2-3 MED of UV (n = 20), epidermal PD-L1 was induced in 70% of subjects after 24 h (P = 0.0001). SKH-1 mice exposed to acute UV also showed significant epidermal PD-L1 induction at 16, 24 and 48 h. A time- and dose-dependent induction of PD-L1 was confirmed in cultured human keratinocytes after UV, which was markedly reduced in the presence of MEK/ERK, JNK or STAT3 inhibitors. These findings suggest that UV induces upregulation of PD-L1 through established, pharmacologically targetable stress-signaling pathways in keratinocytes.
• Geiger, J. L., Cedars, E. D., Zang, Y., Daniel, N. P., Li, H., Grandis, J. R., Centuori, S. M., Daniel, J. E., & Bauman, J. E. (2021). Clinical trials optimizing investigator and self‐collection of buccal cells for RNA yield. Laryngoscope Investigative Otolaryngology.
• Tapia, E., Villa-Guillen, D. E., Chalasani, P., Centuori, S., Roe, D. J., Guillen-Rodriguez, J., Huang, C., Galons, J. P., Thomson, C. A., Altbach, M., Trujillo, J., Pinto, L., Martinez, J. A., Algotar, A. M., & Chow, H. S. (2021). A randomized controlled trial of metformin in women with components of metabolic syndrome: intervention feasibility and effects on adiposity and breast density. Breast cancer research and treatment, 190(1), 69-78.
  More info

  Obesity is a known risk factor for post-menopausal breast cancer and may increase risk for triple negative breast cancer in premenopausal women. Intervention strategies are clearly needed to reduce obesity-associated breast cancer risk.
• Sweeney, N. W., Gomes, C. J., De Armond, R., Centuori, S. M., Parthasarathy, S., & Martinez, J. D. (2019). Hypoxia Suppresses High Fat Diet-Induced Steatosis And Development Of Hepatic Adenomas. Hypoxia (Auckland, N.Z.), 7, 53-63.
  More info

  Nonalcoholic fatty liver disease (NAFLD) is considered the most common form of silent liver disease in the United States and obesity is associated with increased risk of NAFLD. Obstructive sleep apnea (OSA) which is common in obese individuals is associated with a greater incidence of NAFLD, which in turn, increases the risk for hepatocellular carcinoma (HCC). It is unclear how obesity, OSA and NAFLD interrelate nor how they collectively contribute to an increased risk for developing HCC.
• Centuori, S. M., Gomes, C. J., Kim, S. S., Putnam, C. W., Larsen, B. T., Garland, L. L., Mount, D. W., & Martinez, J. D. (2018). Double-negative (CD27IgD) B cells are expanded in NSCLC and inversely correlate with affinity-matured B cell populations. Journal of translational medicine, 16(1), 30.
  More info

  The presence of B cells in early stage non-small cell lung cancer (NSCLC) is associated with longer survival, however, the role these cells play in the generation and maintenance of anti-tumor immunity is unclear. B cells differentiate into a variety of subsets with differing characteristics and functions. To date, there is limited information on the specific B cell subsets found within NSCLC. To better understand the composition of the B cell populations found in NSCLC we have begun characterizing B cells in lung tumors and have detected a population of B cells that are CD79ACD27IgD. These CD27IgD (double-negative) B cells have previously been characterized as unconventional memory B cells and have been detected in some autoimmune diseases and in the elderly population but have not been detected previously in tumor tissue.
• Gomes, C. J., Harman, M. W., Centuori, S. M., Wolgemuth, C. W., & Martinez, J. D. (2018). Measuring DNA content in live cells by fluorescence microscopy. Cell division, 13, 6.
  More info

  Live-cell fluorescence microscopy (LCFM) is a powerful tool used to investigate cellular dynamics in real time. However, the capacity to simultaneously measure DNA content in cells being tracked over time remains challenged by dye-associated toxicities. The ability to measure DNA content in single cells by means of LCFM would allow cellular stage and ploidy to be coupled with a variety of imaging directed analyses. Here we describe a widely applicable nontoxic approach for measuring DNA content in live cells by fluorescence microscopy. This method relies on introducing a live-cell membrane-permeant DNA fluorophore, such as Hoechst 33342, into the culture medium of cells at the end of any live-cell imaging experiment and measuring each cell's integrated nuclear fluorescence to quantify DNA content. Importantly, our method overcomes the toxicity and induction of DNA damage typically caused by live-cell dyes through strategic timing of adding the dye to the cultures; allowing unperturbed cells to be imaged for any interval of time before quantifying their DNA content. We assess the performance of our method empirically and discuss adaptations that can be implemented using this technique.
• Gomes, C. J., Centuori, S. M., Harman, M. W., Putnam, C. W., Wolgemuth, C. W., & Martinez, J. D. (2017). The induction of endoreduplication and polyploidy by elevated expression of 14-3-3γ. Genes & cancer, 8(11-12), 771-783.
  More info

  Several studies have demonstrated that specific 14-3-3 isoforms are frequently elevated in cancer and that these proteins play a role in human tumorigenesis. 14-3-3γ, an isoform recently demonstrated to function as an oncoprotein, is overexpressed in a variety of human cancers; however, its role in promoting tumorigenesis remains unclear. We previously reported that overexpression of 14-3-3γ caused the appearance of polyploid cells, a phenotype demonstrated to have profound tumor promoting properties. Here we examined the mechanism driving 14-3-3γ-induced polyploidization and the effect this has on genomic stability. Using FUCCI probes we showed that these polyploid cells appeared when diploid cells failed to enter mitosis and subsequently underwent endoreduplication. We then demonstrated that 14-3-3γ-induced polyploid cells experience significant chromosomal segregation errors during mitosis and observed that some of these cells stably propagate as tetraploids when isolated cells were expanded into stable cultures. These data lead us to conclude that overexpression of the 14-3-3γ promotes endoreduplication. We further investigated the role of 14-3-3γ in human NSCLC samples and found that its expression is significantly elevated in polyploid tumors. Collectively, these results suggests that 14-3-3γ may promote tumorigenesis through the production of a genetically unstable polyploid intermediate.
• Centuori, S. M., Garland, L. L., Gomes, C. J., Kim, S., Larsen, B. T., Martinez, J. D., Mount, D. B., & Putnam, C. W. (2016). Abstract 713: Determining the role of tumor-infiltrating B cells in NSCLC. Cancer Research, 76(14_Supplement), 713-713. doi:10.1158/1538-7445.am2016-713
  More info

  Recent studies in human non-small cell lung cancer (NSCLC) have shown that upregulation of B cell-associated genes strongly correlate with early stage patient survival. After analyzing a gene expression database of lung tumors we showed that CD79A, a pan-B cell marker, had the strongest predictive value, suggesting that B cells are playing a crucial role in NSCLC immunity. In order to evaluate this we first examined where this genetic signature was originating from. We observed that patients with high levels of B cell-related genes also showed high numbers of CD79A+ B cells intimately associated with the tumor, but not being expressed by tumor cells themselves. A closer look at tumor-infiltrating B cells (TIL-B cells) by IHC and flow cytometry of fresh patient tumor samples has confirmed their presence and allowed us to begin elucidating their phenotype. Interestingly, we have found that not all early stage patients have detectable levels of TIL-B cells, but in those that do, TIL-B cells represent a marked proportion of the lymphocytic infiltration. Further evaluation of T cell populations in the same samples indicate that T cell numbers remain relatively consistent but that the numbers of B-cells, especially CD79A+ B-cells, does vary from patient to patient. These data indicate that CD79A+ TIL-B cells are contributing to the generation of an efficient immune response in some but not all patients, and are greatly influencing disease survivability. This information may allow us to stratify patients into low and high risk groups based on the presence or absence of TIL-B cells, respectively. Citation Format: Sara M. Centuori, Samuel Kim, Cecil Gomes, Charles Putnam, David Mount, Linda Garland, Brandon Larsen, Jesse D. Martinez. Determining the role of tumor-infiltrating B cells in NSCLC. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 713.
• Centuori, S. M., Gomes, C. J., Harman, M. W., Martinez, J. D., & Wolgemuth, C. W. (2016). Abstract 3591: Expression of 14-3-3 gamma stabilizes polyploidization in NSCLC cells. Cancer Research, 76(14_Supplement), 3591-3591. doi:10.1158/1538-7445.am2016-3591
  More info

  In normal lung tissue the expression levels of 14-3-3 gamma are very low and tightly regulated, however, in cancer it is evident that 14-3-3 gamma9s expression patterns become deregulated and significantly elevated. In patients with advanced non-small cell lung cancer (NSCLC), increased expression of this isoform is associated with poorer survival and significantly correlates with lymph node and distant metastasis. These data prompted us to analyze TCGA9s NSCLC gene expression dataset, and it is clear that 14-3-3 gamma9s expression continues to increase in the progression from early to late stage cancers. Taken together, these data suggest that overexpression of 14-3-3 gamma is correlated with a more aggressive tumor phenotype, an observation also seen with breast and hepatocellular carcinoma. The focus of this study is to elucidate the mechanism(s) causing these more aggressive cancer phenotypes. We have previously shown that overexpressing 14-3-3 gamma in human lung cancer cells harboring very low levels of endogenous 14-3-3 gamma and no wildtype p53 results in a stable subpopulation of cells with polyploid DNA content. Interestingly, approximately 40% of lung adenocarcinomas present with hyper-triploid karyotypes, and even a higher percentage, 40-60%, have inactivation of p53. It is well established that polyploid tumors have the capacity to increase tumorigenicity by allowing resistance to conventional therapies and also permitting elevated tolerance to chromosomal instability (CIN). This leads us to hypothesize that in the absence of p53, NSCLC tumors overexpressing 14-3-3 gamma result in a polyploid population of cells that may be influencing the aggressiveness of the tumor. Further in vitro analysis of these 14-3-3 gamma induced tetraploid cells show that they have a prolonged mitosis with significantly more lagging chromosomes in anaphase than their diploid counterparts, indicating an increase in chromosomal instability (CIN). After isolating isogenic tetraploid clones with or without 14-3-3 gamma expression, the stability of the tetraploid cell state was assessed. Clones not expressing 14-3-3 gamma quickly reverted back to a pseudo-diploid state, whereas overexpression of 14-3-3 gamma significantly prolonged the tolerance of tetraploidy and eventually resulted in an aneuploid cell state. Our data suggests that overexpression of 14-3-3 gamma increases tumorigenicity through the stabilization of a polyploid cell state. Citation Format: Cecil J. Gomes, Michael Harman, Sara Centuori, Charles Wolgemuth, Jesse Martinez. Expression of 14-3-3 gamma stabilizes polyploidization in NSCLC cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3591.
• Centuori, S. M., Gomes, C. J., Trujillo, J., Borg, J., Brownlee, J., Putnam, C. W., & Martinez, J. D. (2016). Deoxycholic acid mediates non-canonical EGFR-MAPK activation through the induction of calcium signaling in colon cancer cells. Biochimica et biophysica acta, 1861(7), 663-70.
  More info

  Obesity and a western diet have been linked to high levels of bile acids and the development of colon cancer. Specifically, increased levels of the bile acid deoxycholic acid (DCA), an established tumor promoter, has been shown to correlate with increased development of colorectal adenomas and progression to carcinoma. Herein we investigate the mechanism by which DCA leads to EGFR-MAPK activation, a candidate mechanism by which DCA may promote colorectal tumorigenesis. DCA treated colon cancer cells exhibited strong and prolonged activation of ERK1/2 when compared to EGF treatment alone. We also showed that DCA treatment prevents EGFR degradation as opposed to the canonical EGFR recycling observed with EGF treatment. Moreover, the combination of DCA and EGF treatment displayed synergistic activity, suggesting DCA activates MAPK signaling in a non-canonical manner. Further evaluation showed that DCA treatment increased intracellular calcium levels and CAMKII phosphorylation, and that blocking calcium with BAPTA-AM abrogated MAPK activation induced by DCA, but not by EGF. Finally we showed that DCA-induced CAMKII leads to MAPK activation through the recruitment of c-Src. Taken together, we demonstrated that DCA regulates MAPK activation through calcium signaling, an alternative mechanism not previously recognized in human colon cancer cells. Importantly, this mechanism allows for EGFR to escape degradation and thus achieve a constitutively active state, which may explain its tumor promoting effects.
• Centuori, S. M., Garland, L. L., Gomes, C. J., Kim, S., Martinez, J. D., Mount, D. B., & Putnam, C. W. (2015).

  Abstract 1299: Tumor-infiltrating B cells are predictive of human lung squamous cell survival

  . Immunology, 75(15_Supplement), 1299-1299. doi:10.1158/1538-7445.am2015-1299
• Centuori, S. M., Gomes, C. J., Harman, M. W., & Martinez, J. D. (2015). Abstract 2066: Aberrant upregulation of 14-3-3 gamma promotes mononucleated polyploidization in human lung cancers. Cancer Research, 75(15_Supplement), 2066-2066. doi:10.1158/1538-7445.am2015-2066
• Trad, M., Gautheron, A., Fraszczak, J., Alizadeh, D., Larmonier, C., LaCasse, C. J., Centuori, S., Audia, S., Samson, M., Ciudad, M., Bonnefoy, F., Lemaire-Ewing, S., Katsanis, E., Perruche, S., Saas, P., & Bonnotte, B. (2015). T Lymphocyte Inhibition by Tumor-Infiltrating Dendritic Cells Involves Ectonucleotidase CD39 but Not Arginase-1. BioMed research international, 2015, 891236.
  More info

  T lymphocytes activated by dendritic cells (DC) which present tumor antigens play a key role in the antitumor immune response. However, in patients suffering from active cancer, DC are not efficient at initiating and supporting immune responses as they participate to T lymphocyte inhibition. DC in the tumor environment are functionally defective and exhibit a characteristic of immature phenotype, different to that of DC present in nonpathological conditions. The mechanistic bases underlying DC dysfunction in cancer responsible for the modulation of T-cell responses and tumor immune escape are still being investigated. Using two different mouse tumor models, we showed that tumor-infiltrating DC (TIDC) are constitutively immunosuppressive, exhibit a semimature phenotype, and impair responder T lymphocyte proliferation and activation by a mechanism involving CD39 ectoenzyme.
• Young, G. M., Radhakrishnan, V. M., Centuori, S. M., Gomes, C. J., & Martinez, J. D. (2015). Comparative analysis of 14-3-3 isoform expression and epigenetic alterations in colorectal cancer. BMC cancer, 15, 826.
  More info

  The 14-3-3 family is a group of intracellular proteins found in all eukaryotic organisms. Humans have seven isoforms that serve as scaffolds to promote interactions of regulatory phospho-proteins involved in many vital cellular processes and previous studies have shown that disturbances in native 14-3-3 levels can contribute significantly to the development of various cancers.
• Centuori, S. M., & Martinez, J. D. (2014). Differential regulation of EGFR-MAPK signaling by deoxycholic acid (DCA) and ursodeoxycholic acid (UDCA) in colon cancer. Digestive diseases and sciences, 59(10), 2367-80.
  More info

  A high-fat diet coincides with increased levels of bile acids. This increase in bile acids, particularly deoxycholic acid (DCA), has been strongly associated with the development of colon cancer. Conversely, ursodeoxycholic acid (UDCA) may have chemopreventive properties. Although structurally similar, DCA and UDCA present different biological and pathological effects in colon cancer progression. The differential regulation of cancer by these two bile acids is not yet fully understood. However, one possible explanation for their diverging effects is their ability to differentially regulate signaling pathways involved in the multistep progression of colon cancer, such as the epidermal growth factor receptor (EGFR)-mitogen-activated protein kinase (MAPK) pathway. This review will examine the biological effects of DCA and UDCA on colon cancer development, as well as the diverging effects of these bile acids on the oncogenic signaling pathways that play a role in colon cancer development, with a particular emphasis on bile acid regulation of the EGFR-MAPK pathway.
• Centuori, S. M., Centuori, S. M., Gomes, C. J., Gomes, C. J., Martinez, J. D., & Martinez, J. D. (2014). Abstract 3509: Overexpression of 14-3-3γ contributes to chromosomal instability in human lung cancer. Cancer Research, 74(19_Supplement), 3509-3509. doi:10.1158/1538-7445.am2014-3509
  More info

  Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Lung cancer is the most common cause of cancer-related deaths, and nearly all lung cancers exhibit genomic instability which results in an abnormal number of chromosomes known as aneuploidy. In many lung cancers, 14-3-3 proteins have been shown to be aberrantly activated or suppressed, which implies that these proteins have potential roles in tumorigenesis. Our lab has demonstrated that over expression of one 14-3-3 family member, 14-3-3γ, in a non-small cell lung cancer cell line leads to an increase in the number of cells that exhibit polyploidy, suggesting that this 14-3-3 protein can disrupt normal chromosome segregation. Additionally, overexpression of 14-3-3γ leads to atypical DNA replication and cell cycle progression. Further evaluation of the polyploid population induced by overexpressing 14-3-3γ revealed that a majority of the cells were multinucleated, often with two or more nuclei of unequal size and morphology. Live cell microscopy shows that this nonlinear marked increase in nuclear content is due to unequal distribution of DNA to the daughter cells upon cellular division, promoting chromosomal instability. Our data indicates that 14-3-3γ may play an important role in maintaining normal diploidy, but when overexpressed, as seen in many lung cancers, can lead to increased levels of chromosomal instability and progression into aneuploidy. Citation Format: Cecil J. Gomes, Sara Centuori, Jesse D. Martinez. Overexpression of 14-3-3γ contributes to chromosomal instability in human lung cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3509. doi:10.1158/1538-7445.AM2014-3509
• Mount, D. W., Putnam, C. W., Centouri, S. M., Manziello, A. M., Pandey, R., Garland, L. L., & Martinez, J. D. (2014). Using logistic regression to improve the prognostic value of microarray gene expression data sets: application to early-stage squamous cell carcinoma of the lung and triple negative breast carcinoma. BMC medical genomics, 7, 33.
  More info

  Numerous microarray-based prognostic gene expression signatures of primary neoplasms have been published but often with little concurrence between studies, thus limiting their clinical utility. We describe a methodology using logistic regression, which circumvents limitations of conventional Kaplan Meier analysis. We applied this approach to a thrice-analyzed and published squamous cell carcinoma (SQCC) of the lung data set, with the objective of identifying gene expressions predictive of early death versus long survival in early-stage disease. A similar analysis was applied to a data set of triple negative breast carcinoma cases, which present similar clinical challenges.
• Centuori, S. M. (2013). Abstract 4002: Differential regulation of the ERGF-MAPK pathway by deoxycholic acid (DCA) and Ursodeoxycholic acid (UDCA) in colon cancer.. Cancer Research, 73(8_Supplement), 4002-4002. doi:10.1158/1538-7445.am2013-4002
  More info

  Obesity and a western diet are risk factors for the development of colorectal cancer and correlate with high levels of bile acids. Specifically, the secondary bile acid deoxycholic acid (DCA) has been shown to act as a tumor promoter in animal studies. Interestingly, the tertiary bile acid Ursodeoxycholic acid (UDCA) was found to have chemopreventive activity in a clinical trial conducted in 1285 individuals with recently resected colorectal adenomas. The mechanism(s) of DCA9s tumor promoting effects and UDCA9s chemopreventive activities are unclear, however DCA and UDCA have been previously shown to regulate EGFR-MAPK signaling in a differential manner. Because this mitogenic pathway has been shown to play a role in colon cancer cell proliferation and survival, we hypothesize that DCA9s tumor promoting effect may stem from its regulation of this mitogenic pathway. We therefore examined the role of DCA in the regulation of the EGFR MAPK pathway in human colon cancer cells as compared to UDCA. Our findings show that DCA can induce ERK1/2 phosphorylation in an EGFR-independent manner in HT-29 colon adenocarcinoma cells, and that this is at least partially dependent on PI3K activation. We also determined that UDCA pretreatment was able to suppress both EGF and DCA-induced EGFR-MAP signaling. By elucidating the mechanism by which DCA and UDCA differentially regulate colon cancer proliferation and survival, we may be able to skew the signaling in colon cancer cells to favor chemoprevention as opposed to tumorgenesis. Citation Format: Sara M. Centuori. Differential regulation of the ERGF-MAPK pathway by deoxycholic acid (DCA) and Ursodeoxycholic acid (UDCA) in colon cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4002. doi:10.1158/1538-7445.AM2013-4002
• Centuori, S. M., Trad, M., LaCasse, C. J., Alizadeh, D., Larmonier, C. B., Hanke, N. T., Kartchner, J., Janikashvili, N., Bonnotte, B., Larmonier, N., & Katsanis, E. (2012). Myeloid-derived suppressor cells from tumor-bearing mice impair TGF-β-induced differentiation of CD4+CD25+FoxP3+ Tregs from CD4+CD25-FoxP3- T cells. Journal of leukocyte biology, 92(5), 987-97.
  More info

  MDSCs and Tregs play an essential role in the immunosuppressive networks that contribute to tumor-immune evasion. The mechanisms by which tumors promote the expansion and/or function of these suppressive cells and the cross-talk between MDSC and Treg remain incompletely defined. Previous reports have suggested that MDSC may contribute to Treg induction in cancer. Herein, we provide evidence that tumor-induced gr-MDSCs, endowed with the potential of suppressing conventional T Lc, surprisingly impair TGF-β1-mediated generation of CD4(+)CD25(+)FoxP3(+) iTregs. Furthermore, gr-MDSCs impede the proliferation of nTregs without, however, affecting FoxP3 expression. Suppression of iTreg differentiation from naïve CD4(+) cells by gr-MDSC occurs early in the polarization process, requires inhibition of early T cell activation, and depends on ROS and IDO but does not require arginase 1, iNOS, NO, cystine/cysteine depletion, PD-1 and PD-L1 signaling, or COX-2. These findings thus indicate that gr-MDSCs from TB hosts have the unanticipated ability to restrict immunosuppressive Tregs.
• Janikashvili, N., LaCasse, C. J., Larmonier, C., Trad, M., Herrell, A., Bustamante, S., Bonnotte, B., Har-Noy, M., Larmonier, N., & Katsanis, E. (2011). Allogeneic effector/memory Th-1 cells impair FoxP3+ regulatory T lymphocytes and synergize with chaperone-rich cell lysate vaccine to treat leukemia. Blood, 117(5), 1555-64.
  More info

  Therapeutic strategies combining the induction of effective antitumor immunity with the inhibition of the mechanisms of tumor-induced immunosuppression represent a key objective in cancer immunotherapy. Herein we demonstrate that effector/memory CD4(+) T helper-1 (Th-1) lymphocytes, in addition to polarizing type-1 antitumor immune responses, impair tumor-induced CD4(+)CD25(+)FoxP3(+) regulatory T lymphocyte (Treg) immunosuppressive function in vitro and in vivo. Th-1 cells also inhibit the generation of FoxP3(+) Tregs from naive CD4(+)CD25(-)FoxP3(-) T cells by an interferon-γ-dependent mechanism. In addition, in an aggressive mouse leukemia model (12B1), Th-1 lymphocytes act synergistically with a chaperone-rich cell lysate (CRCL) vaccine, leading to improved survival and long-lasting protection against leukemia. The combination of CRCL as a source of tumor-specific antigens and Th-1 lymphocytes as an adjuvant has the potential to stimulate efficient specific antitumor immunity while restraining Treg-induced suppression.
• LaCasse, C. J., Janikashvili, N., Larmonier, C. B., Alizadeh, D., Hanke, N., Kartchner, J., Situ, E., Centuori, S., Har-Noy, M., Bonnotte, B., Katsanis, E., & Larmonier, N. (2011). Th-1 lymphocytes induce dendritic cell tumor killing activity by an IFN-γ-dependent mechanism. Journal of immunology (Baltimore, Md. : 1950), 187(12), 6310-7.
  More info

  Dendritic cells (DCs) encompass a heterogeneous population of cells capable of orchestrating innate and adaptive immune responses. The ability of DCs to act as professional APCs has been the foundation for the development and use of these cells as vaccines in cancer immunotherapy. DCs are also endowed with the nonconventional property of directly killing tumor cells. The current study investigates the regulation of murine DC cytotoxic function by T lymphocytes. We provide evidence that CD4(+) Th-1, but not Th-2, Th-17 cells, or regulatory T cells, are capable of inducing DC cytotoxic function. IFN-γ was identified as the major factor responsible for Th-1-induced DC tumoricidal activity. Tumor cell killing mediated by Th-1-activated killer DCs was dependent on inducible NO synthase expression and NO production. Importantly, Th-1-activated killer DCs were capable of presenting the acquired Ags from the killed tumor cells to T lymphocytes in vitro or in vivo. These observations offer new possibilities for the application of killer DCs in cancer immunotherapy.
• Cantrell, J., Larmonier, C., Janikashvili, N., Bustamante, S., Fraszczak, J., Herrell, A., Lundeen, T., J LaCasse, C., Situ, E., Larmonier, N., & Katsanis, E. (2010). Signaling pathways induced by a tumor-derived vaccine in antigen presenting cells. Immunobiology, 215(7), 535-44.
  More info

  We have previously reported on the anti-tumoral potential of a chaperone-rich cell lysate (CRCL) vaccine. Immunization with CRCL generated from tumors elicits specific T and NK cell-dependent immune responses leading to protective immunity in numerous mouse tumor models. CRCL provides both a source of tumor antigens and danger signals leading to dendritic cell activation. In humans, tumor-derived CRCL induces dendritic cell activation and CRCL-loaded dendritic cells promote the generation of cytotoxic T lymphocytes in vitro. The current study was designed to identify the signaling events and modifications triggered by CRCL in antigen presenting cells. Our results indicate that tumor-derived CRCL not only promotes the activation of dendritic cells, but also significantly fosters the function of macrophages that thus appear as major targets of this vaccine. Activation of both cell types is associated with the induction of the MAP kinase pathway, the phosphorylation of STAT1, STAT5 and AKT and with transcription factor NF-kappaB activation in vitro and in vivo. These results thus provide important insights into the mechanisms by which CRCL-based vaccines exert their adjuvant effects on antigen presenting cells.

Proceedings Publications

• Vedantham, S., Tseng, H., Centuori, S. M., Garcia, D. O., Chalasani, P., Chiang, J. A., Roe, D., & Chow, H. (2023). Feasibility of quantitative breast density measurements in obese women with dedicated cone-beam breast CT.. In 2023 Program of the 10th International Breast Density & Cancer Risk Assessment Workshop, a21.

Poster Presentations

• Parsons, K. J., Pinto, P., Parnes, H., Pavlovich, C., Uchio, E., Nguyen, M., Kim, H., Gulley, J., Sater, A., Jamieson, C., Hsu, C., Wojtowicz, M., Schlom, J., Donahue, R., Centuori, S. M., Bailey, S., Bauman, J. E., & Chow, H. (2022, February). Immunotherapy to Prevent Progression on Active Surveillance Study (IPASS): A Phase II Randomized, Double Blind, Controlled Trial of PROSTVAC in Prostate Cancer Patients on Active Surveillance. ASCO. Virtual.
• Pinto, L., Centuori, S. M., Guillen-Rodriguez, J., Roe, D., Tapia, E., Chalasani, P., & Chow, S. (2022, November/Fall). Effects of metformin on breast tissue inflammation in premenopausal women with components of metabolic syndrome. SABCS.
• Bauman, J. E., Hsu, C., Centuori, S. M., Jose, G., Garland, L. L., Ho, E., Bengtson, L., Wojtowicz, M., Szabo, E., & Chow, H. (2021, April). Randomized crossover trial evaluating detoxication of tobacco carcinogens by broccoli seed and sprout extract in heavy smokers. American Association for Cancer Research (AACR),. Virtual Interactive 2021: AACR.
• Bauman, J., Saba, N., Roe, D., Bauman, J., Kaczmar, J., Bhatia, A., Muzaffar, J., Julian, R., Wang, S., Bearelly, S., Baker, A., Steuer, C., Giri, A., Burtness, B., Centuori, S. M., Caulin, C., Saboda, K., Obara, S., & Chung, C. (2021, May/Spring). Randomized, phase II study of ficlatuzumab with or without cetuximab in pan-refractory, advanced head and neck squamous cell carcinoma (HNSCC).
  . ASCO.
• Field, M., Bauman, J. E., & Centuori, S. M. (2021, June). Implementation and Expansion of Cytek cFluor™ Immunoprofiling Kit, 14 Color to 26 Colors. CYTO. Virtual: ISAC.
• Pinto, L., Tapia, E., Villa Guillen, D., Chalasani, P., Centuori, S. M., Roe, D., Guillen, J., Huang, C., Galons, J., Thomson, C. A., Altbach, M. I., Trujillo, J., Martinez, J. A., Algotar, A., & Chow, H. (2021, November). A randomized controlled trial of metformin in women with components of metabolic syndrome: Intervention feasibility and effects on breast density and adiposity. SABCS.
• Tapia, E., Villa Guillen, D., Chalasani, P., Centuori, S. M., Roe, D., Guillen, J., Huang, C., Cordova, C., Pinto, L., & Chow, H. (2021, November). Effect of metformin on metabolic markers associated with breast cancer risk in a Phase II clinical trial in overweight/obese premenopausal women. SABCS. Virtual: AACR.
• Bauman, J., Roe, D., Saba, N., Bauman, J., Kaczmar, J., Burtness, B., Muzaffar, J., Julian, R., Wang, S., Bearelly, S., Baker, A., Steuer, C., Bhatia, A., Giri, A., Caulin, C., Stabile, L., Centuori, S. M., & Chung, C. (2020, May/Spring). Randomized, phase II study of ficlatuzumab with or without cetuximab in patients with pan-refractory, recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC).. ASCO.