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The RAS GTPases KRAS, NRAS and HRAS are well-established cancer driver. RHO GTPases (RHO = RAS homologous) such as RHOA are highly similar in their sequence and structure to RAS proteins, but their functions in cancer are poorly understood. Only ten years ago, mutations in RHO proteins, which, unexpectedly, occur at strikingly different residues than in RAS, and fusion genes of RHO-regulating proteins were discovered in different cancer types. 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 indicate 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, focusing on RHOA- and KRAS-dependent 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. |
