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- W2480262013 abstract "Like oncogenic RAS, the RAS homologues RHOA and RHOB are conventionally thought to support the malignant platform by governing cell structure remodeling by effectors that include the Diaphanous (DIAPH) family formins. RHO-activated DIAPHs generate linear actin filaments (F-actin) that physically support membrane protrusions at the leading edge of migrating cells and the trafficking of growth factor receptors, which are processes that may be required for malignant progression. However, our cellular, genetic, and pharmacological studies argue that both RHO and DIAPHs function as tumor suppressors whose loss of function triggers or augments malignant progression. DIAPH1 and DIAPH3 inhibition, for example, reduces cortical F-actin sufficiently to cause non-apoptotic blebbing. Combined with oncogenic RAS, DIAPH inhibition and blebbing accelerate exosome release. These exosomes have the capacity to foment oncogenesis by seasoning cells of the tumor microenvironment in ways that promote inflammation, survival, immune escape, and metastasis. We have identified a mechanism whereby RAS uses its own guanine-nucleotide releasing protein, SOS, to inhibit DIAPHs and facilitate its own escape within exosomes. Consistent with this idea, pharmacological activation of RHO and DIAPH signaling inhibits tumorigenesis and invasion. RHO and DIAPH agonist/activation strategies may prove to be an effective alternative for impairing RAS-driven oncogenesis where conventional inhibitors of RAS-MAPK signaling have failed or have been met by poorly understood resistance mechanisms. Citation Format: Julie Davis-Turner, Andrew M. Howard, Arthur S. Alberts. Activation of RHO-DIAPH signaling impairs RAS-driven exosome biogenesis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1867." @default.
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- W2480262013 date "2016-07-15" @default.
- W2480262013 modified "2023-09-25" @default.
- W2480262013 title "Abstract 1867: Activation of RHO-DIAPH signaling impairs RAS-driven exosome biogenesis" @default.
- W2480262013 doi "https://doi.org/10.1158/1538-7445.am2016-1867" @default.
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