RHO GTPases (RHO = RAS homologous) like RHOA and RAC1 regulate actin-cytoskeletal-dependent events such as cell migration, cell-cell adhesions, cell-extracellular matrix interactions, cell morphology and cell plasticity. Despite that RHO proteins are highly similar in their sequence and structure to the RAS GTPases (e.g., KRAS, NRAS HRAS), which are well-established cancer driver, it is only poorly understood how RHO GTPases drive cancer growth and the cellular response to cancer drug treatment.
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Only ten years ago, mutations in RHO proteins and fusion genes of RHO-regulating proteins were discovered in different cancer types. Even more surprisingly, the mutational hotspots in RHO GTPases occur at strikingly different residues than in the key cancer driver RAS. Thus, extrapolations from RAS are of limited value and RHO-driven cancers are not well defined and highly lethal. In addition, RHO GTPases play a critical, yet poorly understood role in RAS-mutant cancers, particularly in therapy resistance. Recent studies including from our lab show that RHO GTPases control tumorigenesis beyond their canonical functions as regulators of metastasis and other actin-cytoskeletal-dependent processes. We are only beginning to fully understand the comprehensive role of RHO GTPases in cancer.
The Schaefer Lab aims to identify how RHOA and other RHO GTPases drive cancer development and therapy resistance, with a particular focus on gastric cancer and pancreatic cancer. Our overall goal is to leverage our findings to develop better, precision-medicine-based therapies for these lethal cancers and to improve patient outcomes. We use a multidisciplinary approach including advanced microscopy, functional genomics & proteomics, cancer drug pharmacology, structural biochemistry, patient-derived cell lines & organoids, and mouse models. In addition, we collaborate with clinicians. |
