How can we harness cancer mechanobiology to prevent tumour progression?
Worldwide Cancer Research
University of South Australia
Metastatic breast cancer is currently incurable and new methods to halt invasion and metastasis are an important unmet clinical need. Rho-ROCK signalling in tumour cells is a key arbiter of the paracrine program by which cancers shape their microenvironments. We have established using an in vivo model of mammary cancer, that two key proteins, Creld2 and Ptx3 secreted by progressive breast cancers of all subtypes, mediate the recruitment and polarisation of cancer-associated fibroblasts (CAFs) and tumour-associated macrophages (TAMs). Crucially, these genetically normal cells are brought into the tumour's influence to promote tumour progression. We hypothesise that specific effector pathways downstream of ROCK synergise with tumour mechanobiology to selectively mediate the production and secretion of these paracrine factors. Identifying crucial signalling nodes within these pathways may prove a fertile source of novel approaches to target cancer progression. These studies complement ongoing research to identify the receptors in CAFs and TAMs that mediate the functions of Creld2 and Ptx3.  Here we plan to:  1. Employ an in vivo model of microenvironment education and multiplex immunolabelling approaches to characterise the molecular mechanisms underlying the production and secretion of Ptx3  2. Adapt ex vivo primary cell culture approaches and in vivo functional assays to assess the contributions of ECM stiffness and the tumour secretome to the production of tumour-promoting CAFs and TAMs  3. Employ an alginate-based ex vivo 3D culture system to establish the biological relevance of CRELD2 and PTX3 to the tumour microenvironment of human patient samples.  We believe that this highly innovative approach to understanding the interplay between signalling and mechanobiology in the tumour microenvironment will allow us to identify novel vulnerabilities that permit the targeting of breast and other cancers.
2.1 Biological and endogenous factors