Professor and HHMI Investigator
Ph.D., Massachusetts Institute of Technology, 1994

Modulation of apoptosis; chemosensitivity; senescence by cancer genes

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Cancer arises through an evolutionary process whereby normal cells acquire mutations that erode growth controls, leading to the inappropriate expansion of aberrantly proliferating cells. Such mutations can involve activation of oncogenes or inactivation of tumor-suppressor genes, each contributing new capabilities to the developing cancer cell. However, cancer is not an inevitable consequence of oncogenic mutations; instead, cells acquiring such mutations can be eliminated or kept in check by innate tumor-suppressor programs that can be activated in these damaged cells. Our laboratory studies tumor-suppressor networks controlling apoptosis and senescence and how their disruption influences malignant behavior. We previously showed that apoptosis and cellular senescence are potent barriers to oncogene-driven tumorigenesis and that each contributes to the antitumor action of many chemotherapeutic drugs. Thus, not only do mutations that disrupt apoptosis and senescence promote tumor progression but they can also reduce the efficacy of cancer therapy.

To facilitate our research, we are combining genetic and genomic tools that enable us to explore various aspects of cancer biology in a comprehensive way. We have recently developed mouse cancer models based on the genetic manipulation of stem and progenitor cells ex vivo followed by transplantation of the altered cells into the appropriate organ of syngeneic recipient mice. This approach allows us to study the impact of many genes and gene combinations on tumorigenesis in a “mosaic” setting where tumor-initiating cells are embedded in normal tissues. Furthermore, we have developed powerful methods for using RNAi to suppress gene function in vivo in either a stable or reversible manner. Current efforts strive to integrate mosaic mouse models, RNA interference, and genomics to identify new components of these networks and characterize their impact on tumorigenesis and treatment response. In addition, we are developing new RNAi methods to explore the role of tumor suppressor genes in tumor maintenance, and cell death mechanisms involved in tumor regression.

Please visit the Lowe Lab home page.

Zuber, J., Radtke, I., Pardee, T.S., Zhao, Z., Rappaport, A.R., Luo, W., McCurrach, M.E., Yang, M., Dolan, M.E., Kogan, S.C., Downing, J.R., and Lowe, S.W. 2009. Mouse models of human AML accurately predict chemotherapy response. Genes Dev. 23: 877-879.

Zender, L., Xue, W., Zuber, J., Semighini, C.P., Krasnitz, A., Ma, B., Zender, P., Kubicka, S., Luk, J.M., Schirmacher, P., McCombie, R.W., Wigler, M., Hicks, J., Hannon, G.J., Powers, S., and Lowe S.W. 2008. An oncogenomics-based in vivo RNAi screen identifies new tumor suppressors in liver cancer. Cell 135: 852-864.

Krizhanovsky, V., Yon, M., Dickins, R.A., Hearn, S., Simon, J., Miething, C. Yee, H., Zender, L., and Lowe, S.W. 2008. Senescence of activated stellate cells limits liver fibrosis. Cell 134: 657-667.

Xue, W., Krasnitz, A., Lucito, R., Sordella, R., VanAelst, L., Cordon-Cardo, C., Singer, S., Kuehnel, F., Wigler, M., Powers, S., Zender, L., and Lowe, S.W. 2008. DLC1 is a chromosome 8p tumor suppressor whose loss promotes hepatocellular carcinoma. Genes Dev. 22: 1439-1444.

Xue, W., Zender, L., Miething, C., Dickins, R.A., Hernando, E., Krizhanovsky, V., Cordon-Cardo, C., Lowe, S.W. 2007. Senescence and tumour clearance is triggered by 53 restoration in murine liver carcinomas. Nature 445: 656–660.