Our work thus far has focused on a basic biological question that has broad relevance across cancer biology: why are cancer cells dependent on HSF1, the evolutionarily ancient master transcriptional regulator of the heat shock response (HSR)? The HSR is a powerful adaptive mechanism that enables organisms to survive diverse proteotoxic stressors. We have shown that HSF1 is co-opted by tumor cells to promote their survival, to the detriment of their hosts. We have found that in humans, HSF1 is activated in tumors of diverse origin, in a manner that is distinct from its activation during heat-shock. Our work has also revealed that HSF1 is activated in the cells that comprise the tumor microenvironment and drives a transcriptional program that complements, yet is completely distinct from, the program it drives in adjacent cancer cells. HSF1 activation in the tumor and the tumor microenvironment is strongly associated with metastasis and death in multiple types of cancer. Thus, cancers co-opt the ancient, multifaceted survival functions of HSF1 in multiple ways to enable malignant progression in a manner that has far-reaching therapeutic implications. The mechanisms underlying this phenomenon are unknown and highly relevant to cancer diagnosis and treatment. To address this, I will pursue three aims. In the first aim, I will develop methods to address how HSF1’s complex and multifaceted transcriptional programs affect cell state. In the second aim, I will address how HSF1 activation contributes to poor clinical response. In the third aim, I will define the HSF1-independent alternative network adaptations that occur in tumors that have no detectable HSF1 activity. The data generated from this proposal will increase the depth of our understanding of these systems at the cellular and molecular level and will have immediate clinical implications for human cancers.
|Effective start/end date||7/1/16 → 6/30/19|
- Sidney Kimmel Foundation for Cancer Research (Sidney Kimmel 06/30/2016)
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