| Laboratory Medicine and Pathobiology --- University of Toronto

My lab focuses on colorectal cancer research and specifically colorectal cancer-initiating cells. We are interested in studying clonal cooperation and novel therapeutic strategies. We are also interested in studying the role of the microbiome and how it influences primary tumour growth, as well as, metastases.

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Research

The focus of my research program is to develop a better understanding of the molecular pathways underlying the initiation and maintenance of colorectal cancers (CRCs). It is well established that cells within any given tumour display both functional and phenotypic heterogeneity. Experimental work over the past 50 years has also shown that not all cancer cells are created equal with respect to their ability to drive tumour growth; however, the biological basis for this observation remains to be fully elucidated. Our interest is to identify the molecular pathways responsible for driving tumour growth in the subset of CRC cells enriched for tumour-initiating capacity, also referred to as colorectal cancer-initiating cells (CC-ICs). Through identifying and characterizing the relevant molecular pathways we will also begin to understand the factors capable of modulating these survival pathways. One method we are using to better understand the survival mechanisms used by CC-ICs is through studying the molecular pathways they utilize to evade current chemotherapeutic strategies. By using functional genomic strategies to study CC-ICs, in the context of current chemotherapeutic agents, we are developing a better appreciation for the molecular pathways CC-ICs upregulate when exposed to standard of care chemotherapeutic agents.

To better understand the factors driving CRC initiation we have commensed studies looking at a potential role for commensal bacterial flora in the intestinal tract. Our ability to isolate intracellular bacteria from approximately one half of CRC samples derived from both patients and xenografts has led us to question whether these bacteria are playing a role in driving tumour initiation and/or maintenance. The existence of intracellular bacteria in CRC samples is well established, the question that remains to be answered is whether their presence is functionally relevant. We are interested in determining if commensal bacteria have a role in generating and maintaining CRCs and more specifically, CC-ICs.

Professor

Catherine O’Brien is an Assistant Professor in the Department of Surgery at University Health Network and a Scientist at the Ontario Cancer Institute. She obtained her MD from Queen’s University and completed a General Surgery residency at the University of Western Ontario. Dr.O’Brien subsequently went on to complete a fellowship in surgical oncology at University of Toronto, specializing in gastrointestinal malignancies. During her fellowship she also completed a PhD at the University of Toronto studying cancer stem cells in colorectal cancer. The focus of Dr.O’Brien’s lab is to identify the molecular pathways responsible for driving tumour growth in colorectal cancer. The ultimate goal being to utilize this knowledge to devise improved therapeutic strategies for colorectal cancer.

Publications

Selected list of publications

1. David Roulois, Helen Loo Yau, Rajat Singhania, Yadong Wang, Arnavaz Danesh, Shu Yi Shen, Han Han, Gangning Liang, Trevor J. Pugh, Peter A. Jones, Catherine O’Brien, Daniel D. De Carvalho DNA-demethylating agents target colorectal cancer-initiating cells by activation of MDA5/MAVS/IRF7 pathway. Cell: 2015 Aug 27;162(5):961-73. doi: 10.1016/j.cell.2015.07.056. PubMed PMID:26317465.

2. Chen EC, Karl TA, Kalisky T, Gupta SK, O'Brien CA, Longacre TA, van de Rijn M, Quake SR, Clarke MF, Rothenberg ME. KIT Signaling Promotes Growth of Colon Xenograft Tumors in Mice and is Upregulated in a Subset of Human Colon Cancers. Gastroenterology. 2015 May 27. pii: S0016-5085(15)00769-6. doi:10.1053/j.gastro.2015.05.042. [Epub ahead of print] PubMed PMID: 26026391.

3. Belmont PJ, Jiang P, McKee TD, Xie T, Isaacson J, Baryla NE, Roper J, Sinnamon MJ, Lee NV, Kan JL, Guicherit O, Wouter BG, O’Brien CA, Shields D, Olson P, Vanarsdale T, Weinrich SL, Rejto P, Christensen JG, Fantin VR, Hung KE, Martin ES. Resistance to dual blockage of the kinases PI3K and mTOR in KRAS mutant colorectal cancer models results in combined sensitivity to inhibition of the receptor tyrosine kinase EGFR. Sci Signaling 2014 Nov 11;7(351) PubMed PMID: 25389372.

4. Kreso A, van Galen P, Pedley NM, Lima-Fernandes E, Frelin C, Davis T, Cao L,Baiazitov R, Du W, Sydorenko N, Moon YC, Gibson L, Wang Y, Leung C, Iscove NN, Arrowsmith CH, Szentgyorgyi E, Gallinger S, Dick JE, O'Brien CA. Self-renewal as a therapeutic target in human colorectal cancer. Nat Med. 2014 Jan;20(1):29-36.doi: 10.1038/nm.3418. Epub 2013 Dec 1. PubMed PMID: 24292392.

5. Kreso A* , O'Brien CA * , van Galen P , Gan O , Notta F , Brown AM , Ng K , Ma J , Wienholds E , Dunant C , Pollett A , Gallinger S , McPherson J , Mullighan CG , Shibata D, Dick JE. Variable Clonal Repopulation Dynamics Influence Chemotherapy Response in Colorectal Cancer. Science (New York, N.Y.), 2013 Feb 1;339(6119):543-8. doi: 10.1126/science.1227670. Epub 2012 Dec 13. PubMed PMID: 23239624 *co-first authors

6. Vizeacoumar FJ, Arnold R, Vizeacoumar FS, Chandrashekhar M, Buzina A, Young JT, Kwan JH, Sayad A, Mero P, Lawo S, Tanaka H, Brown KR, Baryshnikova A, Mak AB, Fedyshyn Y, Wang Y, Brito GC, Kasimer D, Makhnevych T, Ketela T, Datti A, Babu M, Emili A, Pelletier L, Wrana J, Wainberg Z, Kim PM, Rottapel R, O'Brien CA, Andrews B, Boone C, Moffat J. A negative genetic interaction map in isogenic cancer cell lines reveals cancer cell vulnerabilities. Mol Syst Biol. 2013 Oct 8;9:696. doi: 10.1038/msb.2013.54. PubMed PMID: 24104479;

7. O’Brien CA*, Kreso A, Ryan P, Hermans K, Gibson L, Wang Y, Tsatsanis A, Gallinger S, Dick JE*. Id1 and Id3 regulate the self-renewal capacity of human colon cancer-initiating cells through p21. Cancer Cell 2012: 21(6):777-792. PubMed 22698409 *co-corresponding authors

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