Arshad Ayyaz

Dr. Arshad Ayyaz, MS, PhD

Positions

Assistant Professor

Faculty of Science, Department of Biological Sciences

Member

Arnie Charbonneau Cancer Institute

Full Member

The Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases

Contact information

Web presence

Phone number

Office: 403.220.8134

Location

Office: BI238D

Background

Educational Background

Postdoc - Stem Cells and Cancer Genetics, Mount Sinai Hospital Toronto, 2021

Postdoc - Immunity and Regeneration Biology, Buck Institute for Research on Aging California, 2015

PhD - Molecular and Cell Biology, University of Strasbourg, 2012

MS - Integrated Cell Biology, Louis Pasteur University France, 2008

Biography

Upon training in mucosal immunity as a doctoral researcher in the group of Dr. Dominique Ferrandon at the Institut de Biologie Moléculaire et Cellulaire (University of Strasbourg, France), I next joined the laboratories of Dr. Heinrich Jasper (Buck Institute for Research on Aging, Novato, California, USA) and Dr. Jeff Wrana (Mount Sinai Hospital, Toronto, Canada) for postdoctoral fellowship and studied how the immune and regenerative responses coordinate with each other during tissue repair, which uncovered several new types of stem cells and revealed a novel conserved mechanism of intestinal regeneration that is regulated by the immune cell-derived developmental cues. My work also revealed that abnormalities in this finely-tuned regeneration process lead to the development of human disease and promote poor clinical outcome.

Research

Areas of Research

Area of Focus
  • Understanding the mechanisms of immune escape in tumor initiating colorectal cancer cells
  • Colorectal Cancer
  • Stem Cells
  • Immunotherapy Resistance
  • Immune Escape
  • Genomic Stress
Area of Research

Last decade has seen immunotherapy emerging as revolutionary anti-cancer treatment. Indeed, early clinical trials found a subset of patients with difficult-to-treat melanoma and lung cancer achieve long-term stable response. Subsequent studies found that these hypermutated cancers express ample peptide neo-antigens and are therefore readily detected as ‘non-self’ and eliminated by the therapeutically stimulated cytotoxic lymphocytes. However, most cancers contain relatively stable genome and do not respond to this treatment. For example, about 85% of all colorectal cancers (CRCs) show microsatellite stability, leading to poor response to immunotherapy. Consequently, a median 5-years survival in CRC patients with metastatic disease remains 12.5% making it a leading cause of cancer deaths globally. Thus, there is an urgent need to understand how transformed tissues evade immunity and find new ways to treat cancer patients. Tumor cells with stem cell-like properties that have long been associated with poor prognosis are now emerging as major players in resistance against immunotherapy, as shown by multiple pre-clinical studies. These cells, often referred to as tumor-initiating cells (TICs), can escape lymphocyte detection despite antigen editing, immune checkpoint inhibition or targeted T cell therapy, suggesting that tumor-mediated intrinsic processes, rather than lymphocyte dysfunction, drive immune escape in several tumors.

Our work is focused on understanding how regenerative somatic cells survive immune surveillance during genotoxic stress, what suppresses accumulation of somatic mutations under these conditions, how rare oncogenic genomic alterations escape these checkpoints, and what components of these mechanisms are hijacked by the transformed tissues which promotes their own growth and survival. We are using 3D organoids, tumor organoid-immune cell co-cultures, single cell-multiomics, functional genomics and targeted genome editing approaches to address these questions. Results from these studies are expected to provide novel therapeutic targets that could be used to develop better combination immunotherapeutic treatments that will improve clinical outcome in cancer patients.

Courses

Course number Course title Semester
CMMB 403 Developmental Biology of Animals Fall 2022
CMMB 413 Human Genetics Winter 2023

Projects

Research and teaching interests

Research interests
Human body is exposed to a large variety of chemical, biological and physical hazards, such as toxins, pathogens, pharmaceuticals, radiation and physical injury, just to name a few. These hazards induce damage to our organs and tissues and thereby adversely influence their function that is vital for survival. Therefore, an episode of tissue injury is generally followed by a rapid and highly organized process of tissue repair and regeneration, and cells that are specialized to perform this duty are called somatic stem cells. These regenerative cells are highly dynamic in nature and respond to several internal and external stimuli, which includes genomic alterations, morphogen signals, inflammatory cytokines, growth factors, metabolites and microbial products.

My laboratory is focused on understanding the molecular, genetic and epigenetic basis of stem cell response during normalcy and stress. To achieve this goal, we are using state-of-the-art genome editing, single cell multiomic technologies, transgenic animal models, and several in vivo and ex vivo 3D tissue culture techniques. Findings from these studies are relevant in regeneration medicine.

Disruption in stem cell function is a single most consequential alteration that associates with many degenerative diseases of the human intestine. This includes inflammatory bowel disease, dysplasia, fibrosis and colon cancer. We are using genetic disease models, transgenic animals, tissues collected from patients and clinical data to understand the mechanisms of disease initiation and progression and identify new ways to improve treatments in the clinic.

Teaching interests
My teaching philosophy is built upon universal principles of equity, diversity and inclusivity, collaborative learning, student engagement and effective feedback.

Publications

Publications

  • Dervovic D, Chen ELY, Malik A, Afiuni S, Boucher J, Berman JM, Teng K, Ayyaz A, Lu YQ, Narimatsu M, Mbamalu, Loganathan S, Martinez S, Tsai R, Lee JB, Zhang L, Wrana J, Roux PP, Jackson HW, Schramek D. In vivo CRISPR screens reveal Serpinb9 and Adam2 as regulators of immune therapy response in lung cancer. Nature Communications 14: 3150 (2023).
  • Ayyaz A, Kumar S, Sangiorgi B, Ghoshal B, Gosio J, Ouladan S, Fink M, Barutcu S, Trcka D, Shen J, Chan K, Wrana JL and Gregorieff A. Single-cell transcriptomes of the regenerating intestine reveal a revival stem cell. Nature 569 (7754), 121-125 (2019).
  • Baghdadi MB, Ayyaz A, Coquenlorge S, Chu B, Kumar S, Streutker C, Wrana JL, Kim TH. Enteric glial cell heterogeneity regulates intestinal stem cell niches. Cell Stem Cell 29 (1): 86-100 (2022).
  • Ayyaz A, Hongjie L and Jasper H. Haemocytes control stem cell activity in the drosophila intestine. Nature Cell Biology 17, 736-748 (2015).
  • Ayyaz A, Attisano L and Wrana JL. Recent advances in understanding contextual TGFβ signaling. F1000 Research 6 (F1000 Faculty Rev.): 749 (2017).
  • Goldsmith JR, Spitofsky N, Zamani A, Hood R, Boggs A, Li X, Li M, Reiner E, Ayyaz A, Etwebi Z, Lu L, Rivera Guzman J, Bou-Dargham MJ, Cathoupolis T, Hakonarson H, Sun H, Wrana JL, Gonzalez MV, Chen YH. TNFAIP8 controls murine intestinal stem cell homeostasis and regeneration by regulating microbiome-induced akt signaling. Nature Communications 11, Article number: 2591 (2020).
  • Sousa-Victor P, Ayyaz A, Yayashi R, Qi Y, Madden DT, Lunyak VV, and Jasper H. Piwi is required to limit exhaustion of aging somatic stem cells. Cell Reports 20 (11): 2527-2537 (2017).
  • Rahme BS, Lestradet M, Venanzio GD, Ayyaz A, Yamba MW, Lazzaro M, Liegeois S, Vescovi EG, Ferrandon D. The fliR gene contributes to the virulence of S. marcescens in a Drosophila intestinal infection model. Scientific Reports 12, 3068 (2022).
  • Ayyaz A and Jasper H. Intestinal inflammation and stem cell homeostasis in aging Drosophila melanogaster. Frontiers in Cellular and Infection Microbiology 3:98 (2013).

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