6th Annual Symposium
Physics of Cancer
September 7-9, 2015
|PoC - Physics of Cancer - Annual Symposium|
The biomechanical and epigenetic regulation of caspase-8 in wound-healing and cancer
Institute for Stem Cell Biology and Regenerative Medicine, National Centre for Biological Sciences, Tata Institute of Fundamental Research,, GKVK, Bellary Road, Bangalore 560065, India
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It has long been appreciated that the molecular understanding of wound healing will offer novel insights into cancer progression, which has striking similarities to an “over-healing wound”. Cancer formation is an exploitation of tissue repair processes where tumor stromal development, cancer cell proliferation, and metastasis closely mimic the inflammatory, proliferative and remodeling phases of the wound healing response. We previously found that the down-regulation of caspase-8 in the epidermis is sufficient to initiate a signaling cascade that mimics the wound healing response in the absence of any tissue damage. These results also uncovered a non-apoptotic role for caspase-8 and suggest that the loss of this protein can fuel many processes that are critical for tumor progression and metastasis. Interestingly, the similarities between cancer and wound healing were extended by recent genome-wide analyses of multiple cancers that revealed mutations in both the active and regulatory regions of caspase-8. However, the mechanisms by which cells sense the injury and how the down-regulation of caspase-8 is achieved in a physiological response or in pathological conditions are largely unknown. Using in vivo and in vitro model systems, we found that DNA methyltransferases (DNMTs) play an important role in the dynamic regulation of caspase-8 and its downstream functions during tissue repair. These results are consistent with reports of elevated DNMT activity in various carcinomas. Moreover, we discovered that changes in intercellular mechanical forces govern the methylation status of caspase-8 through DNMT activation. This observation aligns with increasing data that cancer progression is susceptible to mechanical signals resulting from changes in tissue stiffness. Our findings provide new clues into how the epigenetic regulation of caspase-8 would not only protect cancer stem cells from death signals, but also provide a framework for how they usurp the wound-healing program to promote tumor growth and dissemination.