Caitlin M. Conboy


     Year Entered: 2007

     Degrees Received:
     Wellsley College
     Biological Chemistry major
     B.A., 2003

     Thesis Advisor: David Largaespada, Ph.D.

     Current Research: Characterizing genetic drivers of colorectal cancer

     Colorectal Cancer (CRC) is a genetic disease in which a stepwise
     accumulation of somatic mutations in oncogenes and tumor suppressor
     genes (TSGs) drives tumor initiation and progression. These genetic
     lesions are heterogeneous. Mutations in a few genes are highly-
     penetrant, while the majority of recurrently mutated genes are affected
     in <5% of cases. For example, loss of function of Adenomatous Polyposis Coli (APC), a negative regulator of Wnt signaling, occurs in ~85% of human CRC. Although APC mutations initiate transformation of colonic epithelial cells, secondary mutations are required for progression to invasive CRC. Identifying secondary, low-penetrance mutations and understanding how they cooperate with rate-limiting events will improve our understanding of CRC progression and provide novel candidates for biomarkers and targeted therapeutics. The Largaespada lab has used GI tract-specific transposon insertional mutagenesis in mice to conduct forward genetic screens for colorectal cancer genes. Parallel screens were conducted in mice with wildtype and mutant Apc genotypes (ApcMin/+) to discover oncogenes and TSGs that function independently and in cooperation with APC loss of function. These studies successfully re-identified several known cancer genes, and generated a list of ~100 novel candidates. The aim of my PhD research is to validate and define the role of these candidate genes in tumor development, using an in vitro approach to knock down or overexpress candidates in cell lines derived from CRC or normal colonic epithelium. This study design addresses several questions: Are cancer cells dependent on candidate genes for proliferation, survival or invasive growth? Are candidate genes regulators of Wnt signaling? Are they capable of transforming colonic epithelial cells either independently or in cooperation with APC loss of function? By manipulating candidate genes in cancer and normal-derived cell lines, I hope to identify both positive and negative regulators of multiple processes central to tumorigenesis. These data will highlight functionally relevant candidates for further study and ultimately drug targeting.

Publications Prior to Entering MD/PhD Program:

Wilson MD, Barbosa-Morais NL, Schmidt D, Conboy CM, Vanes L, Tybulewicz VL, Fisher EM, Tavaré S, Odom DT. Species-specific transcription in mice carrying human chromosome 21. Science. 2008;322:434-438.

Conboy CM, Spyrou C, Thorne NP, Wade EJ, Barbosa-Morais NL, Wilson MD, Bhattacharjee A, Young RA, Tavaré S,Lees JA, Odom DT. Cell cycle genes are the evolutionarily conserved targets of the E2F4 transcription factor. PLoS ONE. 2007;2:e1061.

Odom DT, Dowell RD, Jacobsen ES, Gordon W, Danford TW, MacIsaac KD, Rolfe PA, Conboy CM, Gifford DK, Fraenkel E. Tissue-specific transcriptional regulation has diverged significantly between human and mouse.  Nat Genet. 2007;39:730-732.

 Blander G, de Oliveira RM, Conboy CM, Haigis M, Guarente L. Superoxide dismutase 1 knock-down induces senescence in human fibroblasts. J Biol Chem. 2003;278:38966-38969.