Accession Number : AD1020621

Title :   Functional Genomics to Identify Therapeutic Targets in Cancer Stem Cells Using a Novel Murine CRPC Model

Descriptive Note : Technical Report,06 Aug 2013,05 Aug 2015

Corporate Author : The University of Texas MD Anderson Cancer Center Houston United States

Personal Author(s) : Wang,Guocan

Full Text :

Report Date : 01 Nov 2015

Pagination or Media Count : 42

Abstract : Castration resistant prostate cancer (CRPC) still remains as a major clinical challenge, since they are incurable. Prostate stem cells can be the cell of origin for prostate cancers accounting for the development of CRPC. However, the identity of prostate cancer stem cells in CRPC remains elusive. Here I used a metastatic Ptensuppc-/-Smad4suppc-/- mouse prostate cancer model to study the mechanisms for CRPC and the biology of cancer stem cells. I discovered that Ptensuppc-/-Smad4suppc-/- tumors have de novo resistance to ADT as compared to Ptensuppc-/- tumors, although castration did provide some survival benefits for Ptensuppc-/-Smad4suppc-/-mice. Established Ptensuppc-/-Smad4suppc-/- CRPC tumors show an increase in proliferating basal cells, the putative cancer stem cells population in castrated Ptensuppc-/-Smad4suppc-/- prostate tumors. ADT in Ptensuppc-/-Smad4suppc-/- mice may promote massive lung metastasis. Interestingly, by integrative analysis of transcriptomic data I identified pathways that may play a role in the resistance to ADT and cancer stem cells in the Ptensuppc-/-Smad4suppc-/- tumors, such as Hippo/Yap1, and Sox2. Importantly, we identify tumor-intrinsic mechanisms as well as tumor-extrinsic mechanisms which not only promote tumor progression but also castration resistance. Particularly, we identified myeloid-derived suppressor cells (MDSCs) as a key regulator in these processes, which is mediated by the activation of Yap1-Cxcl5-Cxcr2 axis.

Descriptors :   Prostate cancer , mice , models , stem cells , epithelial cells , carcinoma , neoplasms , therapeutics , Resistance(Biology)

Distribution Statement : APPROVED FOR PUBLIC RELEASE