Abstract Oncogenic RAS alters the actin cytoskeleton organization and cell surface morphology, but whether and how this morphogenetic alteration regulates the oncogenesis of RAS remains unknown. RAS activates the RAC1 GTPase, and the latter induces branched actin-rich cell membrane protrusions. In melanoma cells with a hyperactive RAC1 mutant, branched actin-driven lamellipodia were shown to promote cell proliferation by enhancing the inhibition of the NF2 tumor suppressor, illustrating a morphological regulation of human oncogenic signaling. This new finding leads to the question whether branched actin-driven membrane protrusions (BAMPs) regulate the molecular signaling of oncogenic RAS. We used volumetric light sheet microscopy and biochemistry approaches to investigate the role of BAMPs in regulating the molecular signaling of oncogenic KRAS. Using cleared-tissue light sheet microscopy, we observe oncogenic KRAS localized in the BAMPs in mouse xenografts of human pancreatic and lung cancer cells. We found that oncogenic KRAS is enriched in the BAMPs in two dimensional cell culture, and that BAMPs regulate the interaction of oncogenic KRAS with downstream effectors. Specifically, we show that BAMPs enhance the interaction of oncogenic KRAS with the TIAM1 effector, implying a positive feedback loop through which BAMPs self-amplify by enhancing the interaction of upstream regulators that induce BAMPs. Furthermore, we found that BAMPs promote merlin inactivation and cyclin D1 expression downstream of Oncogenic K-RAS, independently of the mitogen activated protein kinase pathway (MAPK). We reveal that, in the absence of BAMPs, cells carrying oncogenic KRAS mutations are unable to attain their full proliferative potential. Overall, we discover a novel role of branched actin-driven cell morphology in promoting the penetrance of oncogenic KRAS, a prevalent human oncogene. Citation Format: Gabriel Muhire Gihana, Bo-Jui Chang, Vasanth Siruvallur Murali, Felix Zhou, Kushal Bhatt, Hazel Borges, Lizbeth Perez Castro, Reto Fiolka, Maralice Conacci-Sorrell, Kevin Dean, Gaudenz Danuser. Branched Actin-driven Cell Membrane Protrusions Regulate Oncogenic KRAS Molecular Signaling abstract. In: Proceedings of the AACR Special Conference in Cancer Research: RAS Oncogenesis and Therapeutics; 2026 Mar 5-8; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Res 2026;86 (5Suppl₁): Abstract nr A030.
Gihana et al. (Thu,) studied this question.