Dr. Patrick Caswell, Wellcome Trust Centre for Cell-Matrix Research, University of Manchester
Tuesday 20th February, 1.00 p.m., Stacey Lecture Theatre 1
The endocytosis of cell surface receptors, and subsequent trafficking through the endocytic system, regulates their ability to switch on downstream signalling modules. It is now clear that endocytosis controls signalling during proliferation, differentiation and migration of cells, and plays an important role in cancer progression. Our work has focused on how the endolysosomal system controls the master regulators of the cytoskeleton, RhoGTPases, in cells migrating in 3D-matrix.
We have shown that Rab11-driven recycling of integrins and co-cargo receptors controls the architecture of F-actin protrusions, by switching the balance of RhoGTPase signalling to favour RhoA activation and formin-dependent filopodia formation to generate actin-spike protrusions (rather than lamellipodia). We believe this pathway promotes metastasis of high grade serous ovarian cancer to the omentum, a fatty peritoneal fold that is the major colonisation site in this form of cancer.
In more recent unpublished work, we have analysed how the rear of the cell actively translocates as cells respond to changes in substrate stiffness and migrate and invade. Caveolae, membrane domains associated with buffering membrane tension and with endocytosis, accumulate at the rear of fast moving cells and co-localise with active RhoA. We have not observed internalisation at the cell rear, rather we have evidence that caveolae form in response to lower membrane tension, and caveolae formation promotes RhoA activation to propel the rear for the cell forward.