Background: Cancer cells contend with many obstacles such as metabolic derangements and proteotoxic stress that would normally hamper cell survival and proliferation. Medical interventions impose additional impediments for tumor cell survival. Adaptation to these pressures is essential for cancer survival and proliferation. This proposal is on heat shock factor 1 (HSF1) and understanding how HSF1 is recruited in cancer to support tumorigenesis. HSF1 is the master transcriptional regulator of the heat shock response, a powerful cytoprotective response that drives expression of chaperone proteins. We have recently shown that cancers co-opt HSF1 for efficient growth and that activation of HSF1 is strongly associated with poor clinical outcome. In addition, we have shown that the HSF1 transcriptional network in cancer is distinct from the HSF1 program in heat shock and involves many non-heat shock genes, supporting a rich biological role for HSF1 outside heat shock. A more complete view of the regulation of the HSF1 cancer network and its role in cancer biology is needed. Objective/Hypothesis: There appear to be two distinct but related states of HSF1 activation: one driven by thermal stress (heat shock) but also one driven by the pressure of high rates of cellular proliferation (cancer). The regulation of HSF1 in the two distinct states must therefore be different ? via distinct signaling pathways and distinct protein regulators. In addition, the HSF1 cancer network governs such a potent adaptive response that it may play an important role in helping tumor cells adapt to targeted therapeutics and in developing resistance.
Specific Aims :
Aim 1 : To test the prediction that the HSF1 interactome is different in heat shock and in cancer and to characterize the effects of these HSF1 partner proteins on the activity of HSF1 in cancer.
Aim 2 : To test the prediction that HSF1 and HSP90 (one of the principal chaperones HSF1 regulates) are important for the ability of cancer cells to develop resistance to targeted therapeutics. Study design: I will use a genetically defined panel of cancer lines and affinity purification based approaches to identify the HSF1 interactome in cancer and heat shock and will rigorously validate identified candidate regulators for each state. I will explore if HSF1 and a principal chaperone that it regulates, HSP90, can modify the emergence of resistance to targeted therapeutics for BRAF V600E using melanoma cell lines systems, engineered resistant lines and high complexity DNA bar code libraries that allow us to assess changes in clonal dynamics. Cancer relevance: Identifying the cellular systems that allow cells to withstand and adapt to the challenges of the malignant state is of critical importance for understanding the development and evolution of cancer. Interfering with the mechanisms that support these adaptations may provide a broadly applicable anti-cancer strategy.
Normal cells rely on potent response systems to survive a broad range of otherwise lethal stresses, and cancer cells co-opt and drive the activity of these defense systems so that they can handle the enormous stresses that are a central part of the cancer state. Our studies focus on understanding how cancer cells engage cellular defense mechanisms so that we can devise an entirely new vision for blocking the systems that foster deadly cancers and that allow resistance to anti-cancer therapeutics.
