Functional Genomics to Identify Therapeutic Targets in Cancer Stem Cells Using a Novel Murine CRPC Model
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 Pten<sup>pc-/-Smad4<sup>pc-/- mouse prostate cancer model to study the mechanisms for CRPC and the biology of cancer stem cells. I discovered that Pten<sup>pc-/-Smad4<sup>pc-/- tumors have de novo resistance to ADT as compared to Pten<sup>pc-/- tumors, although castration did provide some survival benefits for Pten<sup>pc-/-Smad4<sup>pc-/-mice. Established Pten<sup>pc-/-Smad4<sup>pc-/- CRPC tumors show an increase in proliferating basal cells, the putative cancer stem cells population in castrated Pten<sup>pc-/-Smad4<sup>pc-/- prostate tumors. ADT in Pten<sup>pc-/-Smad4<sup>pc-/- 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 Pten<sup>pc-/-Smad4<sup>pc-/- 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.
Document Details
- Document Type
- Technical Report
- Publication Date
- Nov 01, 2015
- Accession Number
- AD1020621
Entities
People
- Guocan Wang
Organizations
- University of Texas at Austin