Patrick is Professor of Cancer Cell Biology in the Wellcome Trust Centre for Cell-Matrix Research within the Faculty of Biology, Medicine and Health.

After undergraduate studies at the University of Nottingham, Patrick completed his PhD at the University of Leicester in 2004.  He then moved on to a postdoc at the Beatson Institute for Cancer Research, until taking up his position at the University of Manchester in July 2010 with a Wellcome Trust Career Development Fellowship.

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 5^th 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.

My lab aims to answer the fundamental question of how cells respond to their physical and biochemical extracellular matrix environment, and how the matrix niche is generated in cancer. We focus primarily on cancer cell migration and invasion in 3D-matrix, in particular in ovarian cancer, and how the metastatic matrix niche is formed.

Our current research centres on the functions of vesicle trafficking pathways, in particular the endocytic system, in controlling cell matrix interactions in cancer. This builds on our published work, demonstrating that endocytic trafficking of extracellular matrix receptors (integrins) controls local signalling to facilitate cancer cell migration in complex 3D-environments. We identified a pathway controlled by RabGTPases which rescues active integrins from lysosomes to facilitate invasion (Dozynkiewicz et al Dev. Cell (2012). We also showed that Rab11-driven recycling of integrins and co-cargo receptor tyrosine kinases controls signalling of RhoGTPases (Jacquemet et al. JCB (2015)), and changes the architecture of F-actin in invasive pseudopods to generate filopodial actin-spike protrusions that promote invasive migration of cancer cells (Paul et al. JCB (2015)). In addition, using mathematical modelling approaches, we determined feedback loops that control GTPase activity and cancer cell migration and invasion (Hetmanski et al. (2016) PLOS Comput. Biol.).