Aparna R Sertil

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Courses

Scholarly Contributions

Chapters

• Sertil, A. R. (2014). Hypoxia And Tumor Dormancy: Can The Two Tango?. In Tumor Dormancy And Cellular Quiescence(pp 13-24). Springer Science.
• Bragado, P., Sertil, A. R., & Aguirre-Ghiso, J. (2010). The Tumor Microenvironment.. In Cancer Drug Discovery and Development. Springer Science.
• Baroni, 1. E., Lastro, M. T., Sertil, A. R., Tenenbaum, S. A., Conklin, D. S., & Aguirre-Ghiso, J. A. (2006). Cancer Genomics and Proteomics: Methods and Protocols. In Methods in Molecular Biology, vol. 383. Humana Press Inc.

Journals/Publications

• McCarthy, D. A., Ranganathan, A., Subbaram, S., Flaherty, N. L., Patel, N., Trebak, M., Hempel, N., & Melendez, J. A. (2013). Redox-control of the alarmin, Interleukin-1α. Redox biology, 1(1), 218-25.
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  The pro-inflammatory cytokine Interleukin-1α (IL-1α) has recently emerged as a susceptibility marker for a wide array of inflammatory diseases associated with oxidative stress including Alzheimer's, arthritis, atherosclerosis, diabetes and cancer. In the present study, we establish that expression and nuclear localization of IL-1α are redox-dependent. Shifts in steady-state H2O2 concentrations (SS-[H2O2]) resulting from enforced expression of manganese superoxide dismutase (SOD2) drive IL-1α mRNA and protein expression. The redox-dependent expression of IL-1α is accompanied by its increased nuclear localization. Both IL-1α expression and its nuclear residency are abrogated by catalase co-expression. Sub-lethal doses of H2O2 also cause IL-1α nuclear localization. Mutagenesis revealed IL-1α nuclear localization does not involve oxidation of cysteines within its N terminal domain. Inhibition of the processing enzyme calpain prevents IL-1α nuclear localization even in the presence of H2O2. H2O2 treatment caused extracellular Ca(2+) influx suggesting oxidants may influence calpain activity indirectly through extracellular Ca(2+) mobilization. Functionally, as a result of its nuclear activity, IL-1α overexpression promotes NF-kB activity, but also interacts with the histone acetyl transferase (HAT) p300. Together, these findings demonstrate a mechanism by which oxidants impact inflammation through IL-1α and suggest that antioxidant-based therapies may prove useful in limiting inflammatory disease progression.
• Bragado, P., Estrada, Y., Sosa, M. S., Avivar-Valderas, A., Cannan, D., Genden, E., Teng, M., Ranganathan, A. C., Wen, H., Kapoor, A., Bernstein, E., & Aguirre-Ghiso, J. A. (2012). Analysis of marker-defined HNSCC subpopulations reveals a dynamic regulation of tumor initiating properties. PloS one, 7(1).
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  Head and neck squamous carcinoma (HNSCC) tumors carry dismal long-term prognosis and the role of tumor initiating cells (TICs) in this cancer is unclear. We investigated in HNSCC xenografts whether specific tumor subpopulations contributed to tumor growth. We used a CFSE-based label retentions assay, CD49f (α6-integrin) surface levels and aldehyde dehydrogenase (ALDH) activity to profile HNSCC subpopulations. The tumorigenic potential of marker-positive and -negative subpopulations was tested in nude (Balb/c nu/nu) and NSG (NOD.Cg-Prkdc(scid) Il2rg(tm1Wjl)/SzJ) mice and chicken embryo chorioallantoic membrane (CAM) assays. Here we identified in HEp3, SQ20b and FaDu HNSCC xenografts a subpopulation of G0/G1-arrested slow-cycling CD49f(high)/ALDH1A1(high)/H3K4/K27me3(low) subpopulation (CD49f+) of tumor cells. A strikingly similar CD49f(high)/H3K27me3(low) subpopulation is also present in primary human HNSCC tumors and metastases. While only sorted CD49f(high)/ALDH(high), label retaining cells (LRC) proliferated immediately in vivo, with time the CD49f(low)/ALDH(low), non-LRC (NLRC) tumor cell subpopulations were also able to regain tumorigenic capacity; this was linked to restoration of CD49f(high)/ALDH(high), label retaining cells. In addition, CD49f is required for HEp3 cell tumorigenicity and to maintain low levels of H3K4/K27me3. CD49f+ cells also displayed reduced expression of the histone-lysine N-methyltransferase EZH2 and ERK1/2 phosphorylation. This suggests that although transiently quiescent, their unique chromatin structure is poised for rapid transcriptional activation. CD49f- cells can "reprogram" and also achieve this state eventually. We propose that in HNSCC tumors, epigenetic mechanisms likely driven by CD49f signaling dynamically regulate HNSCC xenograft phenotypic heterogeneity. This allows multiple tumor cell subpopulations to drive tumor growth suggesting that their dynamic nature renders them a "moving target" and their eradication might require more persistent strategies.
• Sertil, A. R. (2012). Analysis of marker-defined HNSCC subpopulations reveals a plastic regulation of tumor initiating properties.. PLOS One.
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  Bragado, P, Estrada, Y, Sosa M, Avivar-Valderas, A, Cannan, D, Ranganathan, AC, Genden, E, Teng, M, Wen, H, Kapoor, K, Bernstein, E, Aguirre-Ghiso
• Adam, A. P., George, A., Schewe, D., Bragado, P., Iglesias, B. V., Ranganathan, A. C., Kourtidis, A., Conklin, D. S., & Aguirre-Ghiso, J. A. (2009). Computational identification of a p38SAPK-regulated transcription factor network required for tumor cell quiescence. Cancer research, 69(14).
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  The stress-activated kinase p38 plays key roles in tumor suppression and induction of tumor cell dormancy. However, the mechanisms behind these functions remain poorly understood. Using computational tools, we identified a transcription factor (TF) network regulated by p38alpha/beta and required for human squamous carcinoma cell quiescence in vivo. We found that p38 transcriptionally regulates a core network of 46 genes that includes 16 TFs. Activation of p38 induced the expression of the TFs p53 and BHLHB3, while inhibiting c-Jun and FoxM1 expression. Furthermore, induction of p53 by p38 was dependent on c-Jun down-regulation. Accordingly, RNAi down-regulation of BHLHB3 or p53 interrupted tumor cell quiescence, while down-regulation of c-Jun or FoxM1 or overexpression of BHLHB3 in malignant cells mimicked the onset of quiescence. Our results identify components of the regulatory mechanisms driving p38-induced cancer cell quiescence. These may regulate dormancy of residual disease that usually precedes the onset of metastasis in many cancers.
• Ranganathan, A. C., Ojha, S., Kourtidis, A., Conklin, D. S., & Aguirre-Ghiso, J. A. (2008). Dual function of pancreatic endoplasmic reticulum kinase in tumor cell growth arrest and survival. Cancer research, 68(9).
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  Pancreatic endoplasmic reticulum kinase (PERK)-eIF2 alpha signaling, a component of the endoplasmic reticulum (ER) stress response, has been proposed as a therapeutic target due to its importance to cell survival in hypoxic tumors. In this study, we show that in addition to promoting survival, PERK can also suppress tumor growth of advanced carcinomas. Our results show that in squamous carcinoma T-HEp3 cells, which display low PERK-eIF2 alpha signaling, inducible activation of an Fv2E-PERK fusion protein results in a strong G(0)-G(1) arrest in vitro. Most importantly, Fv2E-PERK activation, in addition to promoting survival in vitro, inhibits T-HEp3 and SW620 colon carcinoma growth in vivo. Increased PERK activation is linked to enhanced p-eIF2 alpha levels, translational repression, and a decrease in Ki67, pH 3, and cycD1/D3 levels, but not to changes in angiogenesis or apoptosis. Experimental reduction of PERK activity, or overexpression of GADD34 in a spontaneously arising in vivo quiescent variant of HEp3 cells that displays strong basal PERK-eIF2 alpha activation, reverts their quiescent phenotype. We conclude that the growth-inhibitory function of PERK is preserved in tumors and upon proper reactivation can severely inhibit tumor growth through induction of quiescence. This is an important consideration in the development of PERK-based therapies, as its inhibition may facilitate the proliferation of slow-cycling or dormant tumor cells.
• Baroni, T. E., Lastro, M. T., Ranganathan, A. C., Tenenbaum, S. A., Conklin, D. S., & Aguirre-Ghiso, J. A. (2007). Ribonomic and short hairpin RNA gene silencing methods to explore functional gene programs associated with tumor growth arrest. Methods in molecular biology (Clifton, N.J.), 383.
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  In this chapter, we present an approach using genomic and ribonomic profiling to investigate functional gene programs in a tumor growth model. To reach this goal, ribonomic profiling was combined with RNA interference in a tumor dormancy model. Strategies merging functional genomic technologies are outlined for the identification of novel posttranscriptionally regulated targets of p38 to show that they are functionally linked to the induction or interruption of cellular growth in cancer. In the first section of this chapter, we describe a method for the detection of mRNA subsets associated with RNA-binding proteins such as hnRNP A1 using (1) immunopurification of mRNA-protein complexes, from either whole cell lysates or subcellular fractions and (2) gene expression arrays to find those mRNAs bound to hnRNP A1. In the second section, short hairpin RNA technology was used to create a library of shRNAs that target p38 induced mRNAs expression libraries are utilized to "knockdown" the genes identified in the first section. Finally, this library of gene candidates is evaluated in vivo to address their functional role in the induction or maintenance of dormancy.
• Sequeira, S. J., Ranganathan, A. C., Adam, A. P., Iglesias, B. V., Farias, E. F., & Aguirre-Ghiso, J. A. (2007). Inhibition of proliferation by PERK regulates mammary acinar morphogenesis and tumor formation. PloS one, 2(7).
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  Endoplasmic reticulum (ER) stress signaling can be mediated by the ER kinase PERK, which phosphorylates its substrate eIF2alpha. This in turn, results in translational repression and the activation of downstream programs that can limit cell growth through cell cycle arrest and/or apoptosis. These responses can also be initiated by perturbations in cell adhesion. Thus, we hypothesized that adhesion-dependent regulation of PERK signaling might determine cell fate. We tested this hypothesis in a model of mammary acini development, a morphogenetic process regulated in part by adhesion signaling. Here we report a novel role for PERK in limiting MCF10A mammary epithelial cell proliferation during acinar morphogenesis in 3D Matrigel culture as well as in preventing mammary tumor formation in vivo. We show that loss of adhesion to a suitable substratum induces PERK-dependent phosphorylation of eIF2alpha and selective upregulation of ATF4 and GADD153. Further, inhibition of endogenous PERK signaling during acinar morphogenesis, using two dominant-negative PERK mutants (PERK-DeltaC or PERK-K618A), does not affect apoptosis but results instead in hyper-proliferative and enlarged lumen-filled acini, devoid of proper architecture. This phenotype correlated with an adhesion-dependent increase in translation initiation, Ki67 staining and upregulation of Laminin-5, ErbB1 and ErbB2 expression. More importantly, the MCF10A cells expressing PERKDeltaC, but not a vector control, were tumorigenic in vivo upon orthotopic implantation in denuded mouse mammary fat pads. Our results reveal that the PERK pathway is responsive to adhesion-regulated signals and that it is essential for proper acinar morphogenesis and in preventing mammary tumor formation. The possibility that deficiencies in PERK signaling could lead to hyperproliferation of the mammary epithelium and increase the likelihood of tumor formation, is of significance to the understanding of breast cancer.
• Ranganathan, A. C., Adam, A. P., & Aguirre-Ghiso, J. A. (2006). Opposing roles of mitogenic and stress signaling pathways in the induction of cancer dormancy. Cell cycle (Georgetown, Tex.), 5(16).
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  Cancer dormancy is a poorly understood stage of cancer progression. However, the ability to control this step of the disease offers novel therapeutic opportunities. Here we summarize recent findings that implicate the extracellular matrix and adhesion receptor signaling in the escape or induction of tumor dormancy. We further review evidence suggesting that imbalances in the activity ratio of ERK to p38 signaling may determine the fate (i.e., tumorigenicity vs. dormancy) of different carcinoma cells. Special attention is placed on the mechanisms that p38 signaling regulates during the induction of dormancy and how modulation of these pathways may offer a therapeutic opportunity. We also review evidence for a novel drug-resistance mechanism in dormant tumor cells that when blocked may enable killing of dormant tumor cells. Finally, we explore the notion that dormancy of tumor cells may be the result of a selective adaptive response that allows disseminated tumor cells to pause their growth and cope with stress signaling imposed by dissemination and/or treatment until growth can be restored.
• Ranganathan, A. C., Adam, A. P., Zhang, L., & Aguirre-Ghiso, J. A. (2006). Tumor cell dormancy induced by p38SAPK and ER-stress signaling: an adaptive advantage for metastatic cells?. Cancer biology & therapy, 5(7).
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  The mechanisms that determine whether a tumor cell that has disseminated to a secondary site will resume growth immediately, die or enter a state of dormancy are poorly understood. Although tumor dormancy represents a common clinical finding, studying the mechanisms behind this stage of tumor progression has been challenging. Furthermore, it is thought that dormant tumor cells are refractory to chemotherapy due to their lack of proliferation. However, whether this is the only reason for their chemo-resistance remains to be proven. In this review we summarize recent findings that provide a mechanistic explanation about how stress signaling through the p38(SAPK) pathway and ER-stress signaling may coordinate the induction of growth arrest and drug-resistance in a model of squamous carcinoma dormancy. We further discuss how dormant tumor cells may enter this stage to adapt to strenuous conditions that do not favor immediate growth after dissemination. Finally, we propose that this response may recapitulate an evolutionarily conserved program of life-span extension through adaptation and tolerance to stress.
• Ranganathan, A. C., Zhang, L., Adam, A. P., & Aguirre-Ghiso, J. A. (2006). Functional coupling of p38-induced up-regulation of BiP and activation of RNA-dependent protein kinase-like endoplasmic reticulum kinase to drug resistance of dormant carcinoma cells. Cancer research, 66(3).
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  It has been proposed that occult, disseminated metastatic cells are refractory to chemotherapy due to lack of proliferation. We have shown that p38 activation induces dormancy of squamous carcinoma cells. We now show that p38 signaling in these cells activates a prosurvival mechanism via the up-regulation of the endoplasmic reticulum (ER) chaperone BiP and increased activation of the ER stress-activated eukaryotic translation initiator factor 2alpha kinase RNA-dependent protein kinase-like ER kinase (PERK) allowing dormant tumor cells to resist drug toxicity. RNA interference and dominant-negative expression studies revealed that both BiP and PERK signaling promote survival and drug resistance of dormant cells, and that BiP up-regulation prevents Bax activation. We propose that stress-dependent activation of p38 via BiP up-regulation and PERK activation protects dormant tumor cells from stress insults, such as chemotherapy.
• Chiu, S., Lejeune, F., Ranganathan, A. C., & Maquat, L. E. (2004). The pioneer translation initiation complex is functionally distinct from but structurally overlaps with the steady-state translation initiation complex. Genes & development, 18(7).
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  The bulk of cellular proteins derive from the translation of eukaryotic translation initiation factor (eIF)4E-bound mRNA. However, recent studies of nonsense-mediated mRNA decay (NMD) indicate that cap-binding protein (CBP)80-bound mRNA, which is a precursor to eIF4E-bound mRNA, can also be translated during a pioneer round of translation. Here, we report that the pioneer round, which can be assessed by measuring NMD, is not inhibited by 4E-BP1, which is known to inhibit steady-state translation by competing with eIF4G for binding to eIF4E. Therefore, at least in this way, the pioneer round of translation is distinct from steady-state translation. eIF4GI, poly(A)-binding protein (PABP)1, eIF3, eIF4AI, and eIF2alpha coimmunopurify with both CBP80 and eIF4E, which suggests that each factor functions in both modes of translation. Consistent with roles for PABP1 and eIF2alpha in the pioneer round of translation, PABP-interacting protein 2, which is known to destabilize PABP1 binding to poly(A) and inhibit steady-state translation, as well as inactive eIF2alpha, which is also known to inhibit steady-state translation, also inhibit NMD. Polysome profiles indicate that CBP80-bound mRNAs are translated less efficiently than their eIF4E-bound counterparts.
• Lejeune, F., Ranganathan, A. C., & Maquat, L. E. (2004). eIF4G is required for the pioneer round of translation in mammalian cells. Nature structural & molecular biology, 11(10).
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  Nonsense-mediated mRNA decay (NMD) in mammalian cells targets cap-binding protein 80 (CBP80)-bound mRNA during or after a pioneer round of translation. It is unknown whether eukaryotic translation initiation factor 4G (eIF4G) functions in the pioneer round. We show that baculovirus-produced CBP80 and CBP20 independently interact with eIF4GI. The interactions between eIF4G and the heterodimer CBP80/20 suggest that eIF4G has a function in the pioneer initiation complex rather than merely a presence during remodeling to the steady-state complex. First, NMD is inhibited upon eIF4G cleavage by HIV-2 or poliovirus 2A protease. Second, eIF4GI coimmunopurifies with pre-mRNA, indicating that it associates with transcripts before the pioneer round. Third, eIF4G immunopurifies with Upf NMD factors and eIF4AIII, which are constituents of the pioneer translation initiation complex. We propose a model in which eIF4G serves to connect CBP80/20 with other initiation factors during the pioneer round of translation.
• Nelson, K. K., Ranganathan, A. C., Mansouri, J., Rodriguez, A. M., Providence, K. M., Rutter, J. L., Pumiglia, K., Bennett, J. A., & Melendez, J. A. (2003). Elevated sod2 activity augments matrix metalloproteinase expression: evidence for the involvement of endogenous hydrogen peroxide in regulating metastasis. Clinical cancer research : an official journal of the American Association for Cancer Research, 9(1).
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  Elevated manganese superoxide dismutase (Sod2) levels have been reported to be associated with an increased frequency of tumor invasion and metastasis in certain cancers, and the aim of this study is to examine the molecular mechanisms by which this occurs.
• Ranganathan, A. C., Nelson, K. K., Rodriguez, A. M., Kim, K. H., Tower, G. B., Rutter, J. L., Brinckerhoff, C. E., Huang, T. T., Epstein, C. J., Jeffrey, J. J., & Melendez, J. A. (2001). Manganese superoxide dismutase signals matrix metalloproteinase expression via H2O2-dependent ERK1/2 activation. The Journal of biological chemistry, 276(17).
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  Manganese-superoxide dismutase (Sod2) removes mitochondrially derived superoxide (O(2)) at near-diffusion limiting rates and is the only antioxidant enzyme whose expression is regulated by numerous stimuli. Here it is shown that Sod2 also serves as a source of the intracellular signaling molecule H(2)O(2). Sod2-dependent increases in the steady-state levels of H(2)O(2) led to ERK1/2 activation and subsequent downstream transcriptional increases in matrix metalloproteinase-1 (MMP-1) expression, which were reversed by expression of the H(2)O(2)-detoxifying enzyme, catalase. In addition, a single nucleotide polymorphism has recently been identified (1G/2G) at base pair--1607 that creates an Ets site adjacent to an AP-1 site at base pair --1602 and has been shown to dramatically enhance transcription of the MMP-1 promoter. Luciferase promoter constructs containing either the 1G or 2G variation were 25- or 1000-fold more active when transiently transfected into Sod2-overexpressing cell lines, respectively. The levels of MMP-2, -3, and -7 were also increased in the Sod2-overexpressing cell lines, suggesting that Sod2 may function as a "global" redox regulator of MMP expression. In addition, Sod2(-/+) mouse embryonic fibroblasts failed to respond to the cytokine-mediated induction of the murine functional analog of MMP-1, MMP-13. This study provides evidence that the modulation of Sod2 activity by a wide array of pathogenic and inflammatory stimuli may be utilized by the cell as a primary signaling mechanism leading to matrix metalloproteinase expression.

Poster Presentations

• Kumar, S., & Sertil, A. R. (2017, Spring). Activating transcription factor-6 dependent regulation of Rheb-mTOR and NOTCH signaling contributes to chemoresistance in osteosarcoma. Flinn Foundation. COM-PHX.
• Sertil, A. R. (2017, Fall). Microenvironment-Driven Stress Signaling in Cancer Stem Cell, Therapy Resistance, and Dormancy. Inaugural UACC-PHX Cancer Symposium. Phoenix: University of Arizona Cancer Center.
• Yarapureddy, S., & Sertil, A. R. (2017, Spring). Activating Transcription Factor-6a Dependent Regulation of RHEB-mTOR and NOTCH Signaling Contributes to Chemoresistance in Osteosarcoma. Annual Meeting of the American Association of Cell Biology. Washington D.C.
• Yarapureddy, S., & Sertil, A. R. (2017, Winter). INHIBITION OF REGULATED INTRA-MEMBRANE PROTEOLYSIS ENHANCE CHEMOSENSITIVITY IN OSTEOSARCOMA CELLS. Connective Tissue and Sarcoma Society Annual Meeting. Maui, HI: CTOS.
• Hingorani, P., Yarapureddy, S., Asad, O., Kumar, S., Rayes, D., Faraj, J., Dickman, P., & Sertil, A. R. (2015, Fall). Functional coupling of activating transcription factor-6α to osteosarcoma pathogenesis and chemoresistance.. Phoenix Children’s Hospital Research Day. Phoenix Children’s Hospital.
• Yarapureddy, S., Hingorani, P., Asad, O., Kumar, S., & Sertil, A. R. (2015, April 2015). Functional coupling of activating transcription factor-6α to osteosarcoma pathogenesis and chemoresistance.. University of Arizona Cancer Center Retreat. Tucson: University of Arizona Cancer Center.
• Faraj, J., Reyes, D., Hingorani, P., & Sertil, A. R. (2013, Spring). Differential activation of unfolded protein response in metastatic vs. non-metastatic osteosarcoma cells following hypoxia and chemotherapeutic stress.. Basic Medical Sciences Research Retreat. Phoenix, AZ: University of Arizona College of medicine.
• George, A., Aguirre-Ghiso, J., & Sertil, A. R. (2013, Spring). p38SAPK Dependent Nucleo-cytoplasmic Shuttling of hnRNP A1 Promotes Survival of Dormant HEp3 Tumor Cells. Basic Medical Sciences research retreat. Phoenix, AZ: University of Arizona College of medicine.
• Kumar, S., & Sertil, A. R. (2013, Spring). Role of hypoxia and PERK signaling in the regulation of Integrin 6 expression and HNSCC plasticity. Annual Meeting of the American Association of Cell Biology. New Orleans, LA.
• Sertil, A. R., Cabin, J., & Aguirre-Ghiso, J. (2009, Spring). Mechanisms of hypoxia and therapy induced resistance in head and neck squamous cell carcinoma. Head and Neck Cancer Research RetreatTisch Cancer Institute, Department of Otolaryngology, Mount Sinai School of Medicine.
• Sertil, A. R., Ojha, S., Kourtidis, A., Conklin, D. S., & Aguirre-Ghiso, J. (2008, Spring). Dual Function of Pancreatic Endoplasmic Reticulum Kinase in Tumor Cell Growth Arrest and Survival.. Pathobiology of Cancer Workshop. Snowmass, CO.
• Sertil, A. R., Ojha, S., & Aguirre-Ghiso, J. A. (2006, Spring). Suppression of Malignancy as a Function of PERK- eIF2α Activation Pathway.. Mechanisms and Models in Cancer. Cold Spring Harbor Laboratory, Cold Spring Harbor, NY.
• Sertil, A. R., Adam, A., Zhang, L., & Aguirre-Ghiso, J. A. (2005, Spring). Functional Coupling of Endoplasmic Reticulum Signaling to the Induction of Dormancy and Drug Resistance in Human Squamous Carcinoma Cells.. 45th Annual Meeting of the American Association of cell Biology. San Francisco, CA.
• Sertil, A. R., Adam, A., Zhang, L., Sequeira, S. J., & Aguirre-Ghiso, J. A. (2005, Spring). Functional coupling of endoplasmic reticulum signaling to drug resistance of dormant carcinoma cells.. 96th Annual Meeting of the American Association for Cancer Research. Anaheim, CA.
• Sertil, A. R., Nelson, K. K., Rodriguez, A. M., & Melendez, J. A. (2000, Spring). Manganese Superoxide Dismutase- A missing link in the cytokine mediated induction of matrix degrading matrix metalloproteinase-1.. 7th Annual Oxygen Society Meeting. San Diego, CA.

Reviews

• Rausch, M., & Sertil, A. R. (2015. A Stressful Microenvironment: Opposing Effects Of The Endoplasmic Reticulum Stress Response In The Suppression And Enhancement of Adaptive Tumor Immunity(pp 2015 Mar;34(2):104-22.).
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  AbstractThe recent clinical success of immunotherapy in the treatment of certain types of cancer has demonstrated the powerful ability of the immune system to control tumor growth, leading to significantly improved patient survival. However, despite these promising results current immunotherapeutic strategies are still limited and have not yet achieved broad acceptance outside the context of metastatic melanoma. The limitations of current immunotherapeutic approaches can be attributed in part to suppressive mechanisms present in the tumor microenvironment that hamper the generation of robust antitumor immune responses thus allowing tumor cells to escape immune-mediated destruction. The endoplasmic reticulum (ER) stress response has recently emerged as a potent regulator of tumor immunity. The ER stress response is an adaptive mechanism that allows tumor cells to survive in the harsh growth conditions inherent to the tumor milieu such as low oxygen (hypoxia), low pH and low levels of glucose. Activation of ER stress can also alter the cancer cell response to therapies. In addition, the ER stress response promotes tumor immune evasion by inducing the production of protumorigenic inflammatory cytokines and impairing tumor antigen presentation. However, the ER stress response can boost antitumor immunity in some situations by enhancing the processing and presentation of tumor antigens and by inducing the release of immunogenic factors from stressed tumor cells. Here, we discuss the dualistic role of the ER stress response in the modulation of tumor immunity and highlight how strategies to either induce or block ER stress can be employed to improve the clinical efficacy of tumor immunotherapy.