Exploiting membrane dynamics to target the assembly of the metastatic matrix niche in ovarian cancer

BACKGROUND Ovarian cancer has a 5-year survival of only 40% and the outlook is worse for the most common form, high-grade serous ovarian cancer (HGSOC). The major lethal step in HGSOC progression is intracoelomic metastasis. This proposal aims to determine the mechanisms that establish the metastatic niche for HGSOC.

Cancer associated fibroblasts (CAFs) assemble an aberrant matrix to generate the niche that supports HGSOC proliferation and invasion at metastatic sites, but the mechanisms of matrix assembly are unknown.

We hypothesise that plasma membrane tension and vesicle trafficking pathways cooperate to coordinate the delivery and remodelling of matrix molecules at the plasma membrane to generate the metastatic matrix niche.

As metastasis is the primary cause of recurrent disease and patient death, agents that suppress the niche could prolong patient survival and improve quality of life. AIMS We will determine how membrane dynamics coordinate the assembly of the aberrant matrix niche in HGSOC. Two central hypotheses will be tested: 1.

Endocytic recycling pathways carry cargos to the plasma membrane to coordinate the assembly of aberrant matrix. 2. Plasma membrane tension generates local signals that control the cytoskeleton and matrix remodelling. METHODS Established collaborations afford access to metastatic niche cells and tissue from HGSOC patients.

From these we generate primary CAF and metastatic cancer cell cultures to define new mechanisms of aberrant matrix assembly and metastatic niche formation.

Combining cutting edge imaging and proteomics approaches we will determine the endocytic recycling pathways and key cargos that control the generation of the matrix niche by CAFs.

We will reveal the role of membrane tension as a mechanical signal controlling CAF contractility and matrix remodelling, and how the interplay between membrane tension and vesicle trafficking controls CAF behaviour. Using organotypic 3D matrix and mouse models we will define how membrane dynamics supports HGSOC metastasis.

By testing our findings in cells isolated from patients post-chemotherapy, we will explore the function of metastatic niche assembly in resistance to therapy.

HOW THE RESULTS OF THIS RESEARCH WILL BE USED This programme of research will establish new paradigms in HGSOC progression, revealing the mechanisms that underlie aberrant matrix changes and create the metastatic niche for HGSOC.

Interrogating metastatic niche formation using defined patient cells/tissues will establish the clinical potential for targeting matrix assembly to prevent HGSOC metastasis and recurrence.