Cancer Genetics and Functional Genomics
Research Group Head
The work of the Cancer Genetics and Functional genomics research group, directed by Professor Ron Firestein, is focused on using functional and integrated genomic approaches to understanding the basic underpinnings of cancer. Major themes in the lab are listed below:
- Integrative genomic approaches to identify new oncogenic drivers in cancer. Our lab has undertaken sophisticated integrative genomic analyses of colorectal, lung and breast cancers. Using innovative functional genomic screens (CRISPR, shRNA/siRNA) we have uncovered a number of novel oncogenic drivers and dissected their mechanistic input into cancer signalling pathways. Importantly, two of these targets have led to novel small molecule programs that are currently in drug development (CDK8 and LDHB).
- Identification and characterisation of Wnt pathway regulators in colon cancer. While a post-doc at Dana Farber Cancer Institute, we identified CDK8 as a colon cancer oncogene that regulates the Wnt/b-catenin pathway (Firestein R. et al Nature 2008). Since then, my group has developed mouse models and in vivo systems to characterise the function of CDK8 and its paralog, CDK19, in normal homeostasis, development and cancer progression. We have also collaborated with other groups to develop targeted therapies to upstream regulators of the Wnt pathway.
- Elucidation of novel cancer therapeutic biomarkers in preclinical models and clinical samples. Our recent work has identified an important role for enhancer mediated transcripts, i.e. eRNAs, as biomarkers for distinct cancer states and predicting therapeutic response. We are now working to systematically characterise eRNA function and expression in tumours using state of the art genomic editing technologies.
- Therapeutic targeting of the colon cancer epigenome
- Defining the role of Mediator kinase in cancer
- Overcoming chemoresistance in colon cancer
Sooraj D, Sun C, Doan A, Garama DJ, Dannappel MV, Zhu D, Chua H, Mahara S, Wan Hassan W, Croagh D, Prodanovic Z, Gough D, Firestein R. MED12 and BRD4 Cooperate to Sustain Cancer Growth Upon Loss of Mediator Kinase. (in press, Mol Cell).
Wan C, Mahara S, Sun C, Doan A, Chua H, Xu D, Bian J, Li Y, Sooraj D, Cierpicki T, Grembecka J, Firestein R (2021). Genome-scale CRISPR-Cas9 screen of Wnt/β-catenin signalling identifies therapeutic targets for Colorectal Cancer. Sci Adv 7:eabf2567.
McCleland ML, Mesh K, Lorenzana E, Chopra VS, Segal E, Watanabe C, Haley B, Mayba O, Yaylaoglu M, Gnad F, Firestein R (2016) CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest 126:639-652.
In this study, we show for the first time that a long non-coding RNA can be used as a biomarker to predict the efficacy to a targeted epigenetic therapeutic.
Storm EE, Durinck S, de Sousa e Melo F, Tremayne J, Kljavin N, Tan C, Ye X, Chiu C, Pham T, Hongo JA, Bainbridge T, Firestein R, Blackwood E, Metcalfe C, Stawiski EW, Yauch RL, Wu Y, de Sauvage FJ (2016) Targeting PTPRK-RSPO3 colon tumours promotes differentiation and loss of stem-cell function. Nature 529:97-100.
This study describes the development of a novel therapeutic antibody targeting colon cancers marked by RSPO3 translocations and Wnt dependence.
Junttila MR, Mao W, Wang X, Wang BE, Pham T, Flygare J, Yu SF, Yee S, Goldenberg D, Fields C, Eastham-Anderson J, Singh M, Vij R, Hongo JA, Firestein R, Schutten M, Flagella K, Polakis P, Polson AG (2015) Targeting LGR5+ cells with an antibody-drug conjugate for the treatment of colon cancer. Sci Transl Med 7:314.
We show here that targeting the LGR5 stem cell marker is efficacious in preclinical models of colon cancer.
Adler AS, McCleland ML, Yee S, Yaylaoglu M, Hussain S, Cosino E, Quinones G, Modrusan Z, Seshagiri S, Torres E, Chopra VS, Haley B, Zhang Z, Blackwood EM, Singh M, Junttila M, Stephan JP, Liu J, Pau G, Fearon ER, Jiang Z, Firestein R (2014). An integrative analysis of colon cancer identifies an essential function for PRPF6 in tumor growth . Genes Dev 28:1068-1084.
This study showed how the tri-snRNP spliceosome regulates tumour growth via preferential splicing of discrete oncogenic variants.
Jaiswal BS, Kljavin NM, Stawiski EW, Chan E, Parikh C, Durinck S, Chaudhuri S, Pujara K, Guillory J, Edgar KA, Janakiraman V, Scholz RP, Bowman KK, Lorenzo M, Li H, Wu J, Yuan W, Peters BA, Kan Z, Stinson J, Mak M, Modrusan Z, Eigenbrot C, Firestein R, Stern HM, Rajalingam K, Schaefer G, Merchant MA, Sliwkowski MX, de Sauvage FJ, Seshagiri S (2013) Oncogenic ERBB3 mutations in Human Cancers. Cancer Cell 23:603-617.
This study reports the identification of ERBB3 activating mutations in colon and gastric cancer and shows how ERBB3 mutant tumours may be targeted with current therapeutic strategies.