The Reprogramming of Tumor Stroma by HSF1 Is a Potent Enabler of Malignancy
Scherz-Shouval R, Santagata S, Mendillo ML, Sholl LM, Ben-Aharon I, Beck AH, Dias-Santagata D, Koeva M, Stemmer SM, Whitesell L, Lindquist S*. CELL (2014)
We examined the role of transcriptional regulator heat shock factor 1 (HSF1) in stromal cells in order to explore mechanisms of malignant progression in the tumor microenvironment. We found that HSF1 is commonly activated in cancer associated fibroblasts (CAFs). Further, the HSF1 transcriptional program in CAFs is distinct from the HSF1 program in neighboring cancer cells. These data suggest that HSF1 driven reprogramming of tumor stroma enables cancer progression and metastasis, ultimately conferring a poor prognosis.
Tight Coordination of Protein Translation and HSF1 Activation Supports the Anabolic Malignant State
Santagata S, Mendillo ML, Tang Y, Subramanian A, Perley CC, Roche SP, Wong B, Narayan R, Kwon H, Koeva M, Amon A, Golub TR, Porco JA Jr., Whitesell L,* Lindquist S*. SCIENCE (2013).
Our goal was to explore the relationship between metabolic pathways and cancer cell proliferation. Prior research suggests that translational flux is indicative of metabolic state and thus may affect transcriptional regulation. We found that using small molecule inhibitors to block translation globally inactivated heat shock factor 1 (HSF1), and consequently other downstream targets. Further, treatment of malignant and premalignant cells with translation initiation inhibitors impaired cell growth both in vitro and in vivo. These data suggest that HSF1 transcriptional activity may impact cancer proliferation through the modulation of energy metabolism.
HSF1 Drives a Transcriptional Program Distinct from Heat Shock to Support Highly Malignant Human Cancers
Mendillo ML, Santagata S, Koeva M, Bell GW, Hu R, Tamimi RM, Fraenkel E, Ince TA, Whitesell L,* and Lindquist S*. CELL (2012).
Heat-Shock Factor 1 (HSF1), the master regulator of the heat shock response, has been shown to promote tumorigenesis, cancer cell growth, and survival. We found that HSF1 drives a unique transcriptional program in malignancy when compared to heat-shock. The HSF1 cancer program consists of many exclusively cancer-associated genes in addition to a number of heat-shock genes that are uniquely regulated in cancer. A broad range of human cancers show an active HSF1 cancer program, and further, this program is associated with a higher rate of metastasis and death.