Identification of Cell Nonautonomous DNA Damage Responses in the Tumor Microenvironment that Contribute to Cancer Therapy Resistance
Abstract
A major impediment to effective prostate cancer treatment involves the acquired resistance to cytotoxic therapies. Components of the tissue microenvironment are increasingly recognized to profoundly influence tumor cell phenotypes that include susceptibilities to toxic insults. Using a genome-wide analysis of transcriptional responses to genotoxic stress induced by cancer therapeutics, we have identified a spectrum of secreted proteins derived from the tumor microenvironment (TME) that have the potential to modify tumor growth and enhance resistance to DNA-damaging cancer therapeutics. These results suggest a mechanism by which genotoxic therapies given in a cyclical fashion can enhance subsequent treatment resistance through cell non-autonomous effects contributed by the TME. To date, the contributions of individual members of this DNA Damage-associated Secretory Program (DDSP) have not been defined, nor have the signaling mechanisms responsible for propagating the DNA-damage signal(s) been determined. Our objective during this grant period is to test whether treatment-associated DNA damage responses in cells comprising the prostate TME promote tumor growth and subsequent therapy resistance. During this funding period we have: (1) Generated a prostate fibroblast cell line stably expressing SPINK1; (2) Evaluated the impact which SPINK1 activation has upon the growth characteristics of prostate cancer cells lines; (3) Examined how SPINK1 secretion from the microenvironment modulates the response of prostate cancer cells to chemotherapeutics: (4) Begun the evaluation of SPINK1 regulatory pathway; (5) Evaluated the impact of SPINK1 overexpression on tumor growth in-vivo.
Document Details
- Document Type
- Technical Report
- Publication Date
- May 01, 2014
- Accession Number
- ADA601305
Entities
People
- Ryan R. Gordon
Organizations
- Fred Hutchinson Cancer Center