Project Details
Description
It has been widely accepted that distinct epithelial to mesenchymal transition (EMT) phenotype and cancer stem
cell (CSC) properties as well as the immunosuppressive tumor microenvironment (TME) in triple negative breast
cancer (TNBC) subtype account for the aggressive behavior of this disease. Although increased levels of tumor-
infiltrating lymphocytes (TILs) in TNBC predicted better clinical outcome, the majority of these patients display
progressive disease due to the immunosuppressive TME. Although the clinical relevance of TME/pre-metastatic
niche in disease progression has been well recognized, the molecular mechanisms that regulate these
processes remain elusive. Preclinical and clinical data provide compelling evidence that immune cells of myeloid
origin (macrophages, neutrophils, MDSCs) are major components of the TME and predictive of poor prognosis
as well as therapeutic resistance. Therefore, further research is required to understand the underlying molecular
mechanism of formation of immunosuppressive TME/pre-metastatic niche and its role in disease progression
and therapeutic resistance. Our primary objectives in this application are; to determine how stress-induced
HSP70 regulates two fundamental processes; i) protecting tumor cells from cytotoxic cell death by inducing an
epithelial mesenchymal transition (EMT) and cancer stem cell (CSC) phenotype and ii) generating a permissive
microenvironment via the modulation of immunosuppressive myeloid cells. Our central hypothesis is that A20
induced HSP70 in TNBCs protects tumor cells from cytotoxic cell death while inducing an EMT phenotype and
inflammatory cytokines which in turn promote the accumulation of immunosuppressive MDSCs. Therefore,
targeting HSP70 will have a dual activity on tumors and MDSCs. Our rationale is that the identification of
molecular mechanism(s) that sensitize tumor cells to cytotoxic agents while reversing immunosuppression will
improve the effectiveness of currently available therapeutics. We previously demonstrated that growth of tumors
at metastatic sites is dependent of granulocytic MDSCs and suppression of anti-tumor responses and thus
blocking HSP70 in combination with standard of care and/or checkpoint inhibitors could have significant clinical
benefit. Based on these concepts we propose to test our hypothesis by investigating the following specific aims:
Aim 1 will test the hypothesis that a reciprocal A20/HSP70 signaling axis provides cytoprotection to tumor cells
by inducing EMT/CSC phenotype in TNBC subtype. Aim 2 will test the hypothesis that HSP70 regulates
immunosuppressive MDSC induction and acitivity. Aim 3 will determine the molecular mechanism and functional
importance of HSP70 in generation of TME and pre-metastatic niche. At the completion of our proposal, we
expect to elucidate the molecular mechanism by which HSP70 cytoprotects tumor cells from cytotoxic agents by
inducing EMT/CSC phenotype while regulating the immunosuppressive MDSCs in response tumor secreted
cytokines facilitating the tumor progression. It will also determine whether blocking HSP70 potentiates the
efficacy of the chemotherapies and/or immunotherapy in syngeneic mouse models representing TNBC subtype.
Status | Not started |
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