Poster Presentation 29th Lorne Cancer Conference 2017

ROCK-education of cancer-associated fibroblasts in mammary tumours enhances their malignant phenotype and creates a tumour-permissive microenvironment (#126)

Sarah T Boyle 1 , Natasha T Pyne 1 , Marina Kochetkova 1 , Michael S Samuel 1
  1. Centre for Cancer Biology, Adelaide, SA, Australia

Breast cancer is the most commonly diagnosed cancer in females worldwide, and an unmet clinical need exists for novel approaches to target cancers refractory to current treatments. Rho-associated kinase (ROCK) is hyper-activated in most breast cancers, and this pathway has been shown to regulate the tumour microenvironment, promoting cancer progression. Targeting ROCK and/or its regulators and effectors is therefore a potential therapeutic approach against breast cancer.

I have found that hyper-activation of ROCK in a mouse model of breast cancer (PyMT) significantly enhances mammary tumour burden and infiltration of fibroblasts bearing a cancer-associated fibroblast (CAF) phenotype, compared to mice expressing a kinase-dead (KD) version of ROCK. These observations strongly suggest that ROCK regulates the properties of CAFs, which are widely implicated in tumour growth, to promote breast cancer progression. Mammary gland co-engraftment studies demonstrated that ROCK tumour-derived fibroblasts significantly augmented tumour growth from PyMT cancer cells relative to KD tumour-derived counterparts, suggesting that “education” of stromal fibroblasts by ROCK activation in epithelia generates a long-lived, tumour-promoting CAF phenotype. Furthermore, early tumour fibroblasts were highly invasive both towards ROCK-activated mammary epithelial cells and following exposure to media conditioned by ROCK-activated epithelial cells compared to KD controls, suggesting that ROCK educates fibroblasts via paracrine signalling mechanisms.

These results indicate that ROCK promotes mammary tumour progression through the recruitment and education of CAFs. This finding provides a rationale for the development of a novel class of therapies aimed at targeting and impeding the tumour-promoting functions of ROCK-mediated fibroblasts, to normalise the tumour microenvironment.