Yana Zavros
- Professor, Cellular and Molecular Medicine
- Associate Head
- Member of the Graduate Faculty
- Professor, Cancer Biology - GIDP
Contact
- (520) 626-6084
- Life Sciences North, Rm. 450
- Tucson, AZ 85724
- yzavros@arizona.edu
Bio
No activities entered.
Interests
No activities entered.
Courses
2024-25 Courses
-
Pathophys Basics
CMM 427 (Fall 2024) -
Pathophys Basics
CMM 527 (Fall 2024) -
Systems Pathophysiology A
CMM 428 (Fall 2024) -
Systems Pathophysiology A
CMM 528 (Fall 2024)
2023-24 Courses
-
Honors Thesis
NROS 498H (Summer I 2024) -
Adv Topics in Cancer Biology
CBIO 553 (Spring 2024) -
Dissertation
CMM 920 (Spring 2024) -
Honors Thesis
NROS 498H (Spring 2024) -
Mechanisms of Human Disease
CBIO 515 (Spring 2024) -
Mechanisms of Human Disease
CMM 415 (Spring 2024) -
Mechanisms of Human Disease
PATH 415 (Spring 2024) -
Mechanisms of Human Disease
PATH 515 (Spring 2024) -
Pathophys Basics
CMM 527 (Spring 2024) -
Research
CMM 900 (Spring 2024) -
Thesis
CMM 910 (Spring 2024) -
Art of Scientific Comm
CMM 603 (Fall 2023) -
Dissertation
CMM 920 (Fall 2023) -
Pathophys Basics
CMM 427 (Fall 2023) -
Pathophys Basics
CMM 527 (Fall 2023) -
Research
CMM 900 (Fall 2023) -
Systems Pathophysiology A
CMM 428 (Fall 2023) -
Systems Pathophysiology A
CMM 528 (Fall 2023) -
Systems Pathophysiology B
CMM 429 (Fall 2023) -
Systems Pathophysiology B
CMM 529 (Fall 2023) -
Thesis
CMM 910 (Fall 2023)
2022-23 Courses
-
Thesis
CMM 910 (Summer I 2023) -
Adv Topics in Cancer Biology
CBIO 553 (Spring 2023) -
Dissertation
CMM 920 (Spring 2023) -
Pathophys Basics
CMM 527 (Spring 2023) -
Research
CMM 900 (Spring 2023) -
Research
MCB 900 (Spring 2023) -
Scientific Communication
CMM 597 (Spring 2023) -
Scientific Grantsmanship
IMB 521 (Spring 2023) -
Thesis
CMM 910 (Spring 2023) -
Thesis
MCB 910 (Spring 2023) -
Art of Scientific Comm
CMM 603 (Fall 2022) -
Directed Research
MCB 792 (Fall 2022) -
Dissertation
CMM 920 (Fall 2022) -
Pathophys Basics
CMM 427 (Fall 2022) -
Pathophys Basics
CMM 527 (Fall 2022) -
Research
CMM 900 (Fall 2022) -
Systems Pathophysiology A
CMM 428 (Fall 2022) -
Systems Pathophysiology A
CMM 528 (Fall 2022) -
Systems Pathophysiology B
CMM 429 (Fall 2022) -
Systems Pathophysiology B
CMM 529 (Fall 2022) -
Thesis
CMM 910 (Fall 2022) -
Thesis
MCB 910 (Fall 2022)
2021-22 Courses
-
Art of Scientific Comm
CMM 603 (Summer I 2022) -
Thesis
CMM 910 (Summer I 2022) -
Adv Topics in Cancer Biology
CBIO 553 (Spring 2022) -
Honors Thesis
MCB 498H (Spring 2022) -
Pathophys Basics
CMM 527 (Spring 2022) -
Research
CMM 900 (Spring 2022) -
Scientific Grantsmanship
IMB 521 (Spring 2022) -
Thesis
CMM 910 (Spring 2022) -
Honors Thesis
MCB 498H (Fall 2021) -
Pathophys Basics
CMM 427 (Fall 2021) -
Pathophys Basics
CMM 527 (Fall 2021) -
Research
CMM 900 (Fall 2021) -
Systems Pathophysiology A
CMM 428 (Fall 2021) -
Systems Pathophysiology A
CMM 528 (Fall 2021) -
Systems Pathophysiology B
CMM 429 (Fall 2021) -
Systems Pathophysiology B
CMM 529 (Fall 2021) -
Thesis
CMM 910 (Fall 2021)
2020-21 Courses
-
Thesis
CMM 910 (Summer I 2021) -
Adv Topics in Cancer Biology
CBIO 553 (Spring 2021) -
Pathophys Basics
CMM 527 (Spring 2021) -
Research
CMM 900 (Spring 2021) -
Scientific Grantsmanship
IMB 521 (Spring 2021) -
Thesis
CMM 910 (Spring 2021) -
Pathophys Basics
CMM 527 (Fall 2020) -
Research
CMM 900 (Fall 2020) -
Systems Pathophysiology A
CMM 528 (Fall 2020) -
Systems Pathophysiology B
CMM 529 (Fall 2020) -
Thesis
CMM 910 (Fall 2020)
2019-20 Courses
-
Thesis
CMM 910 (Summer I 2020) -
Directed Research
MCB 792 (Spring 2020) -
Directed Rsrch
MCB 392 (Spring 2020) -
Honors Independent Study
MCB 399H (Spring 2020) -
Scientific Grantsmanship
IMB 521 (Spring 2020) -
Thesis
CMM 910 (Spring 2020) -
Thesis
CMM 910 (Fall 2019)
Scholarly Contributions
Chapters
- Zavros, Y. (2021). Epithelial and Immune Cell Responses to Helicobacter pylori That Shape the Gastric Tumor Microenvironment. In Physiology in Health and Disease: Inflammation, Infection, and Microbiome in Cancers(pp 978-3-030-67950-7, 466984_1_En, (Chapter 6)). Springer Nature.
- Zavros, Y. (2021). Research and Clinical Applications of Targeting Gastric Neoplasms. In In vivo and in vitro models of gastric cancer.
Journals/Publications
- Allenspach, K., Zavros, Y., Elbadawy, M., Zdyrski, C., & Mochel, J. P. (2023). Leveraging the predictive power of 3D organoids in dogs to develop new treatments for man and man's best friend. BMC biology, 21(1), 297.
- Mallick, S., Chakrabarti, J., Eschbacher, J., Moraitis, A. G., Greenstein, A. E., Churko, J., Pond, K. W., Livolsi, A., Thorne, C. A., Little, A. S., Yuen, K. C., & Zavros, Y. (2023). Genetically engineered human pituitary corticotroph tumor organoids exhibit divergent responses to glucocorticoid receptor modulators. Translational research : the journal of laboratory and clinical medicine, 256, 56-72.More infoCushing's disease (CD) is a serious endocrine disorder attributed to an adrenocorticotropic hormone (ACTH)-secreting pituitary neuroendocrine tumor (PitNET) that that subsequently leads to chronic hypercortisolemia. PitNET regression has been reported following treatment with the investigational selective glucocorticoid receptor (GR) modulator relacorilant, but the mechanisms behind that effect remain unknown. Human PitNET organoid models were generated from induced human pluripotent stem cells (iPSCs) or fresh tissue obtained from CD patient PitNETs (hPITOs). Genetically engineered iPSC derived organoids were used to model the development of corticotroph PitNETs expressing USP48 (iPSC) or USP8 (iPSC) somatic mutations. Organoids were treated with the GR antagonist mifepristone or the GR modulator relacorilant with or without somatostatin receptor (SSTR) agonists pasireotide or octreotide. In iPSC and iPSC cultures, mifepristone induced a predominant expression of SSTR2 with a concomitant increase in ACTH secretion and tumor cell proliferation. Relacorilant predominantly induced SSTR5 expression and tumor cell apoptosis with minimal ACTH induction. Hedgehog signaling mediated the induction of SSTR2 and SSTR5 in response to mifepristone and relacorilant. Relacorilant sensitized PitNET organoid responsiveness to pasireotide. Therefore, our study identified the potential therapeutic use of relacorilant in combination with somatostatin analogs and demonstrated the advantages of relacorilant over mifepristone, supporting its further development for use in the treatment of Cushing's disease patients.
- Chakrabarti, J., Dua-Awereh, M., Schumacher, M., Engevik, A., Hawkins, J., Helmrath, M. A., & Zavros, Y. (2022). Sonic Hedgehog acts as a macrophage chemoattractant during regeneration of the gastric epithelium. NPJ Regenerative medicine, 7(1), 3.More infoSonic Hedgehog (Shh), secreted from gastric parietal cells, contributes to the regeneration of the epithelium. The recruitment of macrophages plays a central role in the regenerative process. The mechanism that regulates macrophage recruitment in response to gastric injury is largely unknown. Here we tested the hypothesis that Shh stimulates macrophage chemotaxis to the injured epithelium and contributes to gastric regeneration. A mouse model expressing a myeloid cell-specific deletion of Smoothened (LysMcre/+;Smof/f) was generated using transgenic mice bearing loxP sites flanking the Smo gene (Smo loxP) and mice expressing a Cre recombinase transgene from the Lysozyme M locus (LysMCre). Acetic acid injury was induced in the stomachs of both control and LysMcre/+;Smof/f (SmoKO) mice and gastric epithelial regeneration and macrophage recruitment analyzed over a period of 7 days post-injury. Bone marrow-derived macrophages (BM-Mø) were collected from control and SmoKO mice. Human-derived gastric organoid/macrophage co-cultures were established, and macrophage chemotaxis measured. Compared to control mice, SmoKO animals exhibited inhibition of ulcer repair and normal epithelial regeneration, which correlated with decreased macrophage infiltration at the site of injury. Bone marrow chimera experiments using SmoKO donor cells showed that control chimera mice transplanted with SmoKO bone marrow donor cells exhibited a loss of ulcer repair, and transplantation of control bone marrow donor cells to SmoKO mice rescued epithelial cell regeneration. Histamine-stimulated Shh secretion in human organoid/macrophage co-cultures resulted in macrophage migration toward the gastric epithelium, a response that was blocked with Smo inhibitor Vismodegib. Shh-induced macrophage migration was mediated by AKT signaling. In conclusion, Shh signaling acts as a macrophage chemoattractant via a Smo-dependent mechanism during gastric epithelial regeneration in response to injury.
- Chakrabarti, J., Pandey, R., Churko, J. M., Eschbacher, J., Mallick, S., Chen, Y., Hermes, B., Mallick, P., Stansfield, B. N., Pond, K. W., Thorne, C. A., Yuen, K. C., Little, A. S., & Zavros, Y. (2022). Development of Human Pituitary Neuroendocrine Tumor Organoids to Facilitate Effective Targeted Treatments of Cushing's Disease. Cells, 11(21).More info(1) Background: Cushing's disease (CD) is a serious endocrine disorder caused by an adrenocorticotropic hormone (ACTH)-secreting pituitary neuroendocrine tumor (PitNET) that stimulates the adrenal glands to overproduce cortisol. Chronic exposure to excess cortisol has detrimental effects on health, including increased stroke rates, diabetes, obesity, cognitive impairment, anxiety, depression, and death. The first-line treatment for CD is pituitary surgery. Current surgical remission rates reported in only 56% of patients depending on several criteria. The lack of specificity, poor tolerability, and low efficacy of the subsequent second-line medical therapies make CD a medical therapeutic challenge. One major limitation that hinders the development of specific medical therapies is the lack of relevant human model systems that recapitulate the cellular composition of PitNET microenvironment. (2) Methods: human pituitary tumor tissue was harvested during transsphenoidal surgery from CD patients to generate organoids (hPITOs). (3) Results: hPITOs generated from corticotroph, lactotroph, gonadotroph, and somatotroph tumors exhibited morphological diversity among the organoid lines between individual patients and amongst subtypes. The similarity in cell lineages between the organoid line and the patient's tumor was validated by comparing the neuropathology report to the expression pattern of PitNET specific markers, using spectral flow cytometry and exome sequencing. A high-throughput drug screen demonstrated patient-specific drug responses of hPITOs amongst each tumor subtype. Generation of induced pluripotent stem cells (iPSCs) from a CD patient carrying germline mutation CDH23 exhibited dysregulated cell lineage commitment. (4) Conclusions: The human pituitary neuroendocrine tumor organoids represent a novel approach in how we model complex pathologies in CD patients, which will enable effective personalized medicine for these patients.
- Zavros, Y., & Merchant, J. L. (2022). The immune microenvironment in gastric adenocarcinoma. Nature reviews. Gastroenterology & hepatology, 19(7), 451-467.More infoLike most solid tumours, the microenvironment of epithelial-derived gastric adenocarcinoma (GAC) consists of a variety of stromal cell types, including fibroblasts, and neuronal, endothelial and immune cells. In this article, we review the role of the immune microenvironment in the progression of chronic inflammation to GAC, primarily the immune microenvironment driven by the gram-negative bacterial species Helicobacter pylori. The infection-driven nature of most GACs has renewed awareness of the immune microenvironment and its effect on tumour development and progression. About 75-90% of GACs are associated with prior H. pylori infection and 5-10% with Epstein-Barr virus infection. Although 50% of the world's population is infected with H. pylori, only 1-3% will progress to GAC, with progression the result of a combination of the H. pylori strain, host susceptibility and composition of the chronic inflammatory response. Other environmental risk factors include exposure to a high-salt diet and nitrates. Genetically, chromosome instability occurs in ~50% of GACs and 21% of GACs are microsatellite instability-high tumours. Here, we review the timeline and pathogenesis of the events triggered by H. pylori that can create an immunosuppressive microenvironment by modulating the host's innate and adaptive immune responses, and subsequently favour GAC development.
- Chakrabarti, J., Dua-Awereh, M. B., Holokai, L., & Zavros, Y. (2021). Human Gastrointestinal Organoid Models for Studying Microbial Disease and Cancer. Current topics in microbiology and immunology, 430, 55-75.More infoOne of the major discoveries in stem cell research in the past decade embraces the development of "organs in a dish," also known as "organoids." Organoids are three-dimensional cellular structures derived from primary stem cells of different organ-specific cell types which are capable of self-renewal and maintenance of the parental lineages. Researchers have developed in vitro organoid models to mimic in vivo host-microbial interactions and disease. In this review, we focus on the use of gastrointestinal organoids as models of microbial disease and cancer.
- Dawson, R. E., Deswaerte, V., West, A. C., Tang, K., West, A. J., Balic, J. J., Gearing, L. J., Saad, M. I., Yu, L., Wu, Y., Bhathal, P. S., Kumar, B., Chakrabarti, J. T., Zavros, Y., Oshima, H., Klinman, D. M., Oshima, M., Tan, P., & Jenkins, B. J. (2021). STAT3-mediated upregulation of the AIM2 DNA sensor links innate immunity with cell migration to promote epithelial tumourigenesis. Gut.More infoThe absent in melanoma 2 (AIM2) cytosolic pattern recognition receptor and DNA sensor promotes the pathogenesis of autoimmune and chronic inflammatory diseases via caspase-1-containing inflammasome complexes. However, the role of AIM2 in cancer is ill-defined.
- Keilberg, D., Steele, N., Fan, S., Yang, C., Zavros, Y., & Ottemann, K. M. (2021). Gastric Metabolomics Detects Helicobacter pylori Correlated Loss of Numerous Metabolites in Both the Corpus and Antrum. Infection and immunity, 89(2).More infois a chronic bacterial pathogen that thrives in several regions of the stomach, causing inflammation that can vary by site and result in distinct disease outcomes. Whether the regions differ in terms of host-derived metabolites is not known. We thus characterized the regional variation of the metabolomes of mouse gastric corpus and antrum organoids and tissue. The uninfected secreted organoid metabolites differed between the corpus and antrum in only seven metabolites as follows: lactic acid, malic acid, phosphoethanolamine, alanine, uridine, glycerol, and isoleucine. Several of the secreted chemicals were depleted upon infection in both regions, including urea, cholesterol, glutamine, fumaric acid, lactic acid, citric acid, malic acid, and multiple nonessential amino acids. These results suggest a model in which preferentially uses carboxylic acids and amino acids in complex environments, and these are found in both the corpus and antrum. When organoid metabolites were compared to mouse tissue, there was little overlap. The tissue corpus and antrum metabolomes were distinct, including antrum-elevated 5-methoxytryptamine, lactic acid, and caprylic acid, and corpus-elevated phospholipid products. The corpus and antrum remained distinct over an 8-month infection time course. The antrum displayed no significant changes between the time points in contrast to the corpus, which exhibited metabolite changes that were consistent with stress, tissue damage, and depletion of key nutrients, such as glutamine and fructose-6-phosphate. Overall, our results suggest that the corpus and antrum have largely but not completely overlapping metabolomes that change moderately upon infection.
- Rico, K., Duan, S., Pandey, R. L., Chen, Y., Chakrabarti, J. T., Starr, J., Zavros, Y., Else, T., Katona, B. W., Metz, D. C., & Merchant, J. L. (2021). Genome analysis identifies differences in the transcriptional targets of duodenal versus pancreatic neuroendocrine tumours. BMJ open gastroenterology, 8(1).More infoGastroenteropancreatic neuroendocrine tumours (GEP-NETs) encompass a diverse group of neoplasms that vary in their secretory products and in their location within the gastrointestinal tract. Their prevalence in the USA is increasing among all adult age groups.
- Watson, A. W., Grant, A. D., Parker, S. S., Hill, S., Whalen, M. B., Chakrabarti, J., Harman, M. W., Roman, M. R., Forte, B. L., Gowan, C. C., Castro-Portuguez, R., Stolze, L. K., Franck, C., Cusanovich, D. A., Zavros, Y., Padi, M., Romanoski, C. E., & Mouneimne, G. (2021). Breast tumor stiffness instructs bone metastasis via maintenance of mechanical conditioning. Cell reports, 35(13), 109293.More infoWhile the immediate and transitory response of breast cancer cells to pathological stiffness in their native microenvironment has been well explored, it remains unclear how stiffness-induced phenotypes are maintained over time after cancer cell dissemination in vivo. Here, we show that fibrotic-like matrix stiffness promotes distinct metastatic phenotypes in cancer cells, which are preserved after transition to softer microenvironments, such as bone marrow. Using differential gene expression analysis of stiffness-responsive breast cancer cells, we establish a multigenic score of mechanical conditioning (MeCo) and find that it is associated with bone metastasis in patients with breast cancer. The maintenance of mechanical conditioning is regulated by RUNX2, an osteogenic transcription factor, established driver of bone metastasis, and mitotic bookmarker that preserves chromatin accessibility at target gene loci. Using genetic and functional approaches, we demonstrate that mechanical conditioning maintenance can be simulated, repressed, or extended, with corresponding changes in bone metastatic potential.
- Zavros, Y. (2021). DISRUPTION OF HER2-INDUCED PD-L1 EXPRESSION INHIBITS TUMOR CELL IMMUNE EVASION IN PATIENT-DERIVED GASTRIC CANCER ORGANOIDS. Cancers, 7;13(24):6158. doi:10.3390/cancers13246158More infoPMCID: PMC8699100
- Zavros, Y. (2021). Hedgehog Transcriptional Effector GLI Mediates mTOR-Induced PD-L1 Expression in Gastric Cancer Organoids. Cancer Letters.
- Zavros, Y. (2021). Identifying Mechanisms of Gastric Cancer Cell Immune Evasion Using Patient-Derived Tumor Organoid/Immune Cell Co-Cultures. JoVE.
Reviews
- Zavros, Y. (2021. MODELING PANCREATIC PATHOPHYSIOLOGY USING GENOME EDITING OF ADULT STEM CELL-DERIVED AND INDUCED PLURIPOTENT STEM CELL (iPSC) DERIVED ORGANOIDS.