How the cancer associated stroma changes with disease progression, and the role of the Extracellular Matrix (ECM) in influencing chromatin interactions and transcription in Prostate Cancer cells.

At both primary and metastatic sites, activation of tumour-adjacent mesenchymal/stromal cells regulates extracellular matrix (ECM), which then dynamically influences cancer cell progression. Within prostate cancer, specific stromal/mesenchymal subtypes associate with poor patient outcomes. Liver metastases represent a disease stage with the worse patient outcomes and the liver microenvironment represents an under investigated aspect of prostate cancer. We investigate how fibroblasts(in the prostate) and stellate cells (in the liver)produce and modify ECM, and how this influences cancer cells.  

In the liver microenvironment, stellate cells become activated by cancer cells. This activation is enhanced when stellate cells are in the presence of anti-androgens, which are used as therapy for metastatic prostate cancer. Stellate cell/fibroblast activation results in increased mesenchymal proliferation and secretion of ECM.

In both tissue and in vitro models, stellate cells and fibroblasts respond to anti-androgens at a transcriptional and protein level; this regulates (among other pathways) collagen production/density and alterations in the micro-architecture of the ECM. The ECM generated by androgen-stimulated stellate and fibroblasts results in altered proliferation, movement, intracellular signalling pathways, transcriptional profiles, and chromatin enrichment of transcription factors such as AR, YAP1 and SOX2 in the cancer cells. 

Overall, we report an interesting dynamic whereby mesenchymal cells respond to both cancer and cancer treatments to produce a microenvironment which in turn influences cancer cells and may contribute to therapy resistance.