Endocytic regulation of the cytoskeleton
We have recently found that caveolae form at the rear of cells migrating in 3D matrix and during durotaxis when cells move within a 2D gradient of stiffness (Hetmanski et al, in preparation). In and on such substrates of non-uniform stiffness, cells generate higher traction force at the cell front through actomyosin contractility, and as the cell moves forward membrane tension at the cell rear is decreased. This decrease in membrane tension is sensed by caveolae, which form to activate RhoA and drive retraction of the migrating cell rear. This exciting new research direction shows that membrane trafficking regulators (in this case sensing membrane tension changes) control and coordinate the response of cells to their mechanical environment.
RhoA can be activated at the cell rear (through caveolae) and at the cell front (through Rab11-mediated trafficking). However, each generates very different local responses (actomyosin contractility versus actin polymerisation). We hypothesise that caveolae and recycling vesicles act to scaffold the activation of RhoGTPases and differentially link to downstream effector pathways, and this underlies the ability to invoke the appropriate cytoskeletal response in different parts of the migrating cell; contractility and retraction of the rear or actin polymerisation and protrusion at the front.
Function of vesicle trafficking in tumour-stroma interactions
Tumour-stroma interactions control many of the hallmarks of cancer, including proliferation, resistance to therapy, and invasion and metastasis. We have shown that endocytic trafficking regulates the ability of cancer cells to interact with their matrix environment. Because we have established clear links between endocytic recycling within ovarian cancer cells and their ability to invade into collagen and fibronectin-rich matrix, we focus on high grade serous ovarian cancer (HGSOC). Ovarian cancer is the 5th most common cause of cancer-related death in women in the UK, and HGSOC is the most common and lethal form. HGSOC preferentially metastasises to the omentum, and this step is thought to contribute to further dissemination, resistance to therapy and ultimately patient death. We aim to use surgically resected patient tissues to generate cell lines (fibroblasts and cancer cells) and explants determine how HGSOC cells invade into and proliferate within collagen and fibronectin-rich islands of stroma in the omentum, and how fibroblasts create this matrix rich niche for HGSOC cells.