Integrative characterisation of secreted factors involved in intercellular communication between prostate epithelial or cancer cells and fibroblasts
Abstract
Reciprocal interactions between prostate cancer cells and carcinoma‐associated fibroblasts (CAFs) mediate cancer development and progression; however, our understanding of the signalling pathways mediating these cellular interactions remains incomplete. To address this, we defined secretome changes upon co‐culture of prostate epithelial or cancer cells with fibroblasts that mimic bi‐directional communication in tumours. Using antibody arrays, we profiled conditioned media from mono‐ and co‐cultures of prostate fibroblasts, epithelial and cancer cells, identifying secreted proteins that are upregulated in co‐culture compared to mono‐culture. Six of these (CXCL10, CXCL16, CXCL6, FST, PDGFAA, IL‐17B) were functionally screened by siRNA knockdown in prostate cancer cell/fibroblast co‐cultures, revealing a key role for follistatin (FST), a secreted glycoprotein that binds and bioneutralises specific members of the TGF‐β superfamily, including activin A. Expression of FST by both cell types was required for the fibroblasts to enhance prostate cancer cell proliferation and migration, whereas FST knockdown in co‐culture grafts decreased tumour growth in mouse xenografts. This study highlights the complexity of prostate cancer cell–fibroblast communication, demonstrates that co‐culture secretomes cannot be predicted from individual cultures, and identifies FST as a tumour‐microenvironment‐derived secreted factor that represents a candidate therapeutic target.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Jan 27, 2023
- Source ID
- 10.1002/1878-0261.13376
Entities
People
- Anderly C. Chüeh
- Birunthi Niranjan
- Kimberley C. Clark
- Lisa G. Horvath
- Renea A Taylor
- Roger J. Daly
- Yunjian Wu
Organizations
- Chris O’Brien Lifehouse
- Garvan Institute of Medical Research
- Monash University
- National Health and Medical Research Council
- United States Department of Defense
- University of Melbourne
- University of Sydney