Iacovos Michael

At a Glance

• Gene regulatory networks in cancer cell plasticity and metastasis
• MicroRNA signaling pathways and biologically relevant target genes
• Integration of genetic and multi-omic approaches
• Use of genetically engineered mouse cancer models and cancer patient samples
• Preclinical studies in collaboration with clinicians

Short Bio

Dr. Michael earned his MSc in Laboratory Medicine and Pathobiology and Ph.D. in Molecular Genetics at the University of Toronto. He carried out his postdoctoral training in the Swiss Institute of Cancer Research at the École Polytechnique Fédérale de Lausanne, Switzerland, under the mentorship of Dr. Douglas Hanahan, during which he examined the role of miRNAs during tumorigenesis. His work has been published in high profile scientific journals, and recognized by prestigious awards and fellowships, such as from the Canadian Institutes of Health Research and the International Human Frontier Science Program Organization. Dr. Iacovos Michael is currently a Scientist at the Sunnybrook Research Institute, and an Assistant Professor at the University of Toronto.

Research Synopsis

Our overall goal is to dissect the underpinning molecular pathways involved in cancer cell plasticity and metastasis. Cancer cell plasticity has been associated with the development of tumor heterogeneity, acquired resistance to targeted therapies, and metastasis - the leading cause of death of cancer patients. While numerous studies have demonstrated the role of genetic alterations during the initiation of tumorigenesis, recent studies underscore the critical role of non-genetic alterations, such as non-coding RNAs, and the microenvironment during cancer cell plasticity and metastasis.

We have shown that during disease progression, pancreatic neuroendocrine tumors (PanNETs; originating from the islet cells of the pancreas) undergo dedifferentiation, leading to inactivation of mature ß cell gene sets and activation of progenitor cell-like gene sets. The dedifferentiation of PanNETs leads to the rise of a highly invasive and metastatic subtype. Our studies revealed that the miR-181-Meis2-Hmgb3 axis orchestrates PanNETs’ dedifferentiation, and the miR-23b cluster-ALK7 axis plays a key role during metastasis.

Currently, we focus on three major areas of research:

1. Dissecting the role of microRNA-mediated signaling pathways during the dedifferentiation of PanNETs and the neuroendocrine transdifferentiation of epithelial cancers.
2. Delineating the role of the tumor microenvironment during cancer cell plasticity and identifying critical heterotypic cell-cell interactions.
3. Examining the role of cancer cell plasticity during metastasis.

As part of our research, we employ diverse methodologies and models. We use various genetic approaches, such as gain and loss-of-function, and diverse omics approaches, including bulk and single-cell RNA-seq. To recapitulate the different steps of cancer progression, we use genetically engineered mouse models as well as orthotopic and experimental metastasis assays. Finally, our group is grateful to have access to samples collected from cancer patients currently undergoing various treatments at the Odette Cancer Centre at the Sunnybrook Health Sciences Centre, which enables us to perform translational studies.

Recent Publications

1. Saghafinia S^#, Homicsko K, Domenico AD, Wullschleger S, Perren A, Marinoni I, Ciriello G, Michael IP^#*, Hanahan D*. Cancer Cells Retrace a Stepwise Differentiation Program during Malignant Progression. Cancer Discovery. 2021 Oct;11(10):2638-2657. ^#equal contribution, *co-corresponding authors

2.  Michael IP, Saghafinia S, Hanahan D. A set of microRNAs coordinately controls tumorigenesis, invasion, and metastasis. PNAS. 2019 Nov 26;116(48):24184-24195.

3.  Zeng Q, Michael IP, Zhang P, Saghafinia S, Knott G, Jiao W, McCabe BD, Galván JA, Robinson HPC, Zlobec I, Ciriello G, Hanahan D. Synaptic proximity enables NMDAR signalling to promote brain metastasis. Nature. 2019 Sep 18;573(7775):526-531.

4.  Michael IP, Saghafinia S, Tichet M, Zangger N, Marinoni I, Perren A, Hanahan D. ALK7 Signaling Manifests a Homeostatic Tissue Barrier That Is Abrogated during Tumorigenesis and Metastasis. Developmental Cell. 2019 May 6;49(3):409-424.e6.

5.  Allen E, Jabouille A, Rivera LB, Lodewijckx I, Missiaen R, Steri V, Feyen K, Tawney J, Hanahan D, Michael IP, Bergers G. Combined antiangiogenic and anti-PD-L1 therapy stimulates tumor immunity through HEV formation. Sci Transl Med 2017 Apr 12;9(385).