Lindquist Lab--Research--Cancer

Cancer and the Heat Shock Response

Driven by intense selective pressures in their hosts, cancers evolve along a multiplicity of pathways to invasive, metastatic, and drug-resistant phenotypes. The transforming activity of mutant, oncogenic v-Src is an example of such a phenotype. The role of Hsp90 in the evolution of cancers is multifaceted: it promotes the activity of tumor-promoting proteins and allows cells to survive in the face of a load of genetic variation that might otherwise kill them. And, once a critical threshold is reached, it releases new variation to produce more aggressive and invasive phenotypes.

After manipulating Hsp90 function in human cancer cell lines and in mice, we monitor the progression of spontaneous tumors, as well as tumors induced by onocogenes and mutagens, using phenotypic and high-throughput genetic analyses. These multiple mechanisms by which Hsp90 chaperone activity can facilitiate the evolution of new traits provide both a new paradigm for understanding rapid, stepwise evolution and a framework for targeted therapeutic interventions.

HSF1 modulates oncogenesis by orchestrating a diverse network of
cellular functions. (a) With intact HSF1 function, cells accommodate the stressful alterations imposed by either oncogene activation or tumor suppressor inactivation by modulating diverse cellular responses, such as proliferation, survival, signaling
transduction, and metabolism. Ironically, the robustness of a healthy cell is exploited by oncogenic stimuli to accomplish the process of malignant transformation. (b) In contrast, with impaired HSF1, cells are unable to adapt efficiently because of disarrayed cellular responses. As a result, such cells demonstrate relative resistance to malignant transformation (from Dai et al. 2007).

"Cancer Chemotherapy: An Unfolding Story" by Madeline Drexler, Radcliffe Quarterly, Winter 2009

"Protein folding: sculpting evolutionary change, human health, and disease" (FASEB Excellence in Science Award Lecture, ASBMB Annual Meeting, New Orleans, LA, April 2009)

Also see Evolution projects.

Selected Publications on Cancer and the Heat Shock Response

Reviews:

Whitesell L, Lindquist S, 2009. Inhibiting the transcription factor HSF1 as an anticancer strategy. Expert Opinion on Therapeutic Targets 13(4): 469-478 [PDF 576 KB].

Whitesell L and Lindquist SL, 2005. Hsp90 and the Chaperoning of Cancer. Nat. Rev. Cancer 5(10): 761-72. [PDF 436 KB]

Research Papers:

Santagata S, Hu R, Lin NU, Mendillo ML, Collins LC, Hankinson SE, Schnitt SJ, Whitesell W, Tamimi RM, Lindquist S, Ince TA, 2011. High levels of nuclear HSF1 are associated with poor prognosis in breast cancer. Proc Natl Acad Sci USA, 31 Oct, doi: 10/1073/pnas.1115031108 [Epub ahead of print]. [PDF 1.7M]

Dai C, Whitesell L, Rogers AB and Lindquist S, 2007. Heat-shock factor 1 Is a Powerful Multifaceted Modifier of Carcinogenesis. Cell, 130: 1005-1018. [PDF 1.2M]