Oral Presentation The Annual Scientific Meeting of the Endocrine Society of Australia and the Society for Reproductive Biology 2014

The Kallikrein-related serine peptidase, KLK4, regulates the TGFβ1 pathway in the tumour-stroma microenvironment in prostate cancer. (#90)

Ruth Fuhrman-Luck 1 2 , Scott Stansfield 1 2 , Marcus Hastie 3 , Thomas Stoll 3 , Carson Stephens 1 2 , Daniela Loessner 4 , Melanie Lehman 1 2 , Colleen Nelson 1 2 , Jeffrey Gorman 3 , Judith Clements 1 2
  1. Australian Prostate Cancer Research Centre, QLD, Australia
  2. Australian Prostate Cancer Research Centre-Queensland and Institute of Health and Biomedical Innovation, Queensland University of Technology, Translational Research Insitute-QUT, Brisbane, QLD, Australia
  3. QIMR Berghofer Medical Research Institute, Herston, QLD
  4. Institute of Health and Biomedical Innovation, QLD, Australia

Prostate cancer cells reside in a complex stromal microenvironment often referred to as “reactive” stroma which is a critical component of prostate cancer initiation and progression. The mounting evidence for its critical nature has led to increased interest in this niche as a target for new therapeutic approaches. Cancer associated fibroblasts (CAFs) play a key role in this niche regulating the tumour microenvironment. Factors secreted by prostate cancer cells can ‘activate’ non-malignant associated fibroblasts to become CAFs. KLK4 is over-expressed in both localised and bone metastatic prostate cancer and so has the capacity to act as a paracrine factor on the surrounding stroma. The Aim of this study was to elucidate the role of KLK4 in tumour-stroma cross-talk by identifying its substrates in the prostate cancer lines, LNCaP and PC3 (also derived from a bone metastasis) and in the prostate (stromal) fibroblast line WPMY-1. This was accomplished at the protein level utilising the ‘PROtein TOpography Migration Analysis Platform’ (Dix et al., Cell, 2008). Gene expression changes following KLK4 treatment were also assessed by gene microarray analysis. We identified 50 putative novel KLK4 protein substrates, 11 of which directly interact with the growth factor TGFβ1. Strikingly, the most enriched pathway (based on DAVID analysis, p<0.01) following transcriptome analysis of the KLK4-treated cells was the TGFβ1 pathway. KLK4-treated fibroblasts also expressed elevated levels of a number of genes consistent with a CAF genotype. These findings suggest that KLK4 is a critical regulator of the reactive stromal niche, via the TGFβ1 pathway, and a potential novel therapeutic target for prostate cancer.