Research Interests

The Hahn laboratory has developed systematic approaches to discover and characterize mutations that program cancer development in order to derive a deeper understanding of the molecular networks that lead to malignant transformation and to drive the translation of these findings into clinically useful therapeutics. By combining work in experimental cancer models with comprehensive analyses of patient derived tumors, the overarching goal of our research is the development of new types of clinical trials focused on targeting specific cancer targets in selected patients with embedded molecular endpoints.

Our prior work has addressed the regulation of cellular lifespan, both in normal and malignant human cells. Both cell cycle regulatory proteins and telomerase regulate replicative lifespan, and alterations in each of these mechanisms are commonly found in human cancers. Telomerase plays a key role in cellular immortalization; expression of telomerase in many cells is sufficient to achieve immortalization, a hallmark of cancer. Using telomerase to immortalize human cells, we have shown that such immortalized cells are now susceptible to transformation by the combination of oncogene activation and inactivation of tumor suppressor pathways in vitro. Using oncogenes, dominant inhibitors of tumor suppressor proteins, and telomerase, we have now created models of human breast, lung, prostate, and ovarian epithelial cancers of defined genetic constitution that recapitulate many of the characteristics of spontaneously arising human tumors. We are using these models to understand the molecular basis of specific cancer phenotypes including androgen independence in prostate cancer, invasion and metastasis.

In parallel to these studies, we continue to investigate the pathways perturbed by telomerase and SV40 small t antigen in human cell transformation. Our recent work in telomere biology focuses on a new function of telomerase in transformation distinct from its role in immortalization. In addition, we have shown that SV40 small t antigen contributes to transformation by perturbing the serine-threonine phosphatase PP2A, and we are studying the consequences of this interaction for transformation.

With our colleagues at the Broad Institute, we have developed genome scale tools to perform somatic cell genetics in mammalian cells. Specifically, my lab is a founding member of the RNAi Consortium (TRC), which is dedicated to the production, validation, and use of genome scale RNA interference reagents. Together with colleagues in the DFCI Center for Cancer Genome Discovery and Center for Cancer Systems Biology, we have created an integrated cancer genomics platform that combines whole genome methods in patient derived tumors with functional genomic validation studies in experimental models. Our recent pilot studies provide proof-of-principle evidence that these technologies are sufficiently mature to be deployed within the context of a translational effort to discover and validate cancer targets. Our goal is to use this platform to drive the development of new clinical trials focused on targeting specific cancer targets in selected patients with embedded molecular endpoints.