Our laboratory studies tumor-suppressor networks controlling apoptosis and senescence and how their disruption influences malignant behavior.
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.
Previous work in my laboratory has shown 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, 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 by genetically manipulating stem and progenitor cells ex vivo and then transplanting 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 RNA interference (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.
Learn more about Scott Lowe at the Howard Hughes Medical Institute.
Lujambio A, Akkari L, Simon J, Grace D, Bolden JE, Zhao Z, Thapar V, Joyce J, Krizhanovsky V, Lowe SW (2013). Non-cell-autonomous tumor suppression by p53. Cell. 2013 Apr 11;153(2):449-60. doi: 10.1016/j.cell.2013.03.020. Epub 2013 Apr 4.
Aksoy O, Chicas A, Zeng T, Zhao Z, McCurrach M, Wang X, Lowe SW. The atypical E2F family member E2F7 couples the p53 and Rb pathways during cellular senescence. Genes Dev. 2012 Jul 15;26(14):1546-57. doi: 10.1101/gad.196238.112.
Scuoppo C, Miething C, Lindqvist L, Reyes J, Ruse C, Appelmann I, Yoon S, Krasnitz A, Teruya-Feldstein J, Pappin D, Pelletier J, Lowe SW. A tumor suppressor network relying on the polyamine-hypusine axis. Nature. 2012 Jul 12;487(7406):244-8. doi: 10.1038/nature11126.
Zuber J, Shi J, Wang E, Rappaport AR, Herrmann H, Sison EA, Magoon D, Qi J, Blatt K, Wunderlich M, Taylor MJ, Johns C, Chicas A, Mulloy JC, Kogan SC, Brown P, Valent P, Bradner JE, Lowe, SW, Vakoc CR. RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia. Nature. 2011 Aug 3;478(7370):524-8. doi: 10.1038/nature10334.
Premsrirut PK, Dow LE, Kim YK, Malone CD, Scuoppo Cl, Zuber J, Miething C, Dickins RA, Hannon GJ, Lowe SW. A rapid and scalable system for studying gene function in mice using conditional RNA interference. A rapid and scalable system for studying gene function in mice using conditional RNA interference. Cell. 2011 Apr 1;145(1):145-58. doi: 10.1016/j.cell.2011.03.012.
Biologist Scott W. Lowe is an expert on the processes that naturally inhibit cancer development.