My research focuses on the molecular mechanisms that control the Rac protein family, which regulates cell shape, cell movement, oxygen radical formation and gene expression, in particular, the proteins that activate Rac, so-called Rac-GEFs. A few years ago, my lab discovered a new type of Rac-GEF, the P-Rex family, and we have been studying the mechanisms that regulate their activity and their functional roles.
We found that P-Rex family Rac-GEFs are important for the ability of our white blood cells to defend us against bacterial and fungal infections, for the shape and electrical functions of nerve cells that control the coordination of our movements, and for the distribution of skin pigment cells during development. We also participated in studies which showed that the deregulation of the cellular amount or activity of P-Rex family Rac-GEFs contribute to cancer growth and metastasis.
Currently, I am investigating new functional roles of P-Rex and other Rac-GEFs, particularly in inflammatory cells, and exploring new ways of monitoring Rac-GEF activity.
P-Rex2 is a Rac guanine-nucleotide factor (Rac-GEF) that controls glucose homeostasis. This role is thought to be mediated through its adaptor function inhibiting Pten rather than through its Rac-GEF activity, but this remains to be demonstrated. To examine this question, we have investigated the roles of P-Rex2 in glucose homeostasis using Prex2 and catalytically-inactive Prex2 mice. We show that P-Rex2 is required for insulin sensitivity but limits glucose clearance, suppressing glucose uptake into liver and skeletal muscle independently of its catalytic activity. In hepatocytes, P-Rex2 suppresses Glut2 cell surface levels, mitochondrial membrane potential and mitochondrial ATP production. We identify the orphan GPCR Gpr21 as a P-Rex2 target and propose that P-Rex2 limits hepatic glucose clearance by controlling Gpr21 trafficking. In skeletal muscle cells, P-Rex2 suppresses glucose uptake through a separate adaptor function, independently of Gpr21. Additionally, P-Rex2 suppresses insulin secretion by pancreatic islets and plasma insulin levels. Finally, P-Rex2 plays distinct Rac-GEF activity dependent and independent roles in PIP production in liver and skeletal muscle, respectively. Together, our study identifies complex roles of P-Rex2 in glucose homeostasis, mediated through largely GEF-activity independent mechanisms which include the GPCR Gpr21 in hepatocytes and but are not obviously linked to the regulation of Pten.
Metastasis is the spread of cancer cells from primary tumours to distant organs and is the cause of 90% of cancer deaths globally. Metastasizing cancer cells are uniquely vulnerable to immune attack, as they are initially deprived of the immunosuppressive microenvironment found within established tumours. There is interest in therapeutically exploiting this immune vulnerability to prevent recurrence in patients with early cancer at risk of metastasis. Here we show that inhibitors of cyclooxygenase 1 (COX-1), including aspirin, enhance immunity to cancer metastasis by releasing T cells from suppression by platelet-derived thromboxane A (TXA). TXA acts on T cells to trigger an immunosuppressive pathway that is dependent on the guanine exchange factor ARHGEF1, suppressing T cell receptor-driven kinase signalling, proliferation and effector functions. T cell-specific conditional deletion of Arhgef1 in mice increases T cell activation at the metastatic site, provoking immune-mediated rejection of lung and liver metastases. Consequently, restricting the availability of TXA using aspirin, selective COX-1 inhibitors or platelet-specific deletion of COX-1 reduces the rate of metastasis in a manner that is dependent on T cell-intrinsic expression of ARHGEF1 and signalling by TXA in vivo. These findings reveal a novel immunosuppressive pathway that limits T cell immunity to cancer metastasis, providing mechanistic insights into the anti-metastatic activity of aspirin and paving the way for more effective anti-metastatic immunotherapies.
Metastatic melanoma remains a major clinical challenge. Large-scale genomic sequencing of melanoma has identified bona fide activating mutations in RAC1, which are associated with resistance to BRAF-targeting therapies. Targeting the RAC1-GTPase pathway, including the upstream activator PREX2 and the downstream effector PI3Kβ, could be a potential strategy for overcoming therapeutic resistance, limiting melanoma recurrence, and suppressing metastatic progression. Here, we used genetically engineered mouse models and patient-derived BRAFV600E-driven melanoma cell lines to dissect the role of PREX2 in melanomagenesis and response to therapy. While PREX2 was dispensable for the initiation and progression of melanoma, its loss conferred sensitivity to clinically relevant therapeutics targeting the MAPK pathway. Importantly, genetic and pharmacological targeting of PI3Kβ phenocopied PREX2 deficiency, sensitizing model systems to therapy. These data reveal a druggable PREX2/RAC1/PI3Kβ signaling axis in BRAF-mutant melanoma that could be exploited clinically.