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RhoA wild-type allele loss unleashes the cancer driver function of RhoA E40Q

ABSTRACT: Cancer hotspot mutations of unknown function often obscure the functional understanding of the molecular pathways underlying cancer formation and limit precision medicine progress. Here, we investigated unresolved driver functions of RhoA in Head and neck squamous cell carcinoma (HNSCC). Our investigation reveals that RhoA E40Q is a partial loss-of-function allele which paradoxically promotes tumorigenesis only in the absence of wild-type RhoA. Therefore, mice expressing RhoA E40Q specifically in keratinocytes lacking wild-type RhoA spontaneously developed squamous cell carcinoma and showed defective hair shafts formation. Mechanistically, RhoA E40Q expression in RhoA-deficient cells impaired genome maintenance as shown by increased nuclear foci of gh2AX, a marker for DNA double-strand breaks. This genomic instability was mirrored by reduced cellular fitness upon RhoA E40Q knock-in in MCF10A cells, a phenotype also observed in BRCA2 loss. These convergent data establish RhoA E40Q as an unusual, context-dependent oncogenic driver: a seemingly inactive variant that unleashes its tumor-promoting potential only when the wild-type allele is absent.

ORGANISM(S): Mus musculus

PROVIDER: GSE331033 | GEO | 2026/07/30

REPOSITORIES: GEO

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Project description:The small GTPase RhoA regulates a variety of cellular processes, including cell motility, proliferation, survival and permeability. In addition, there are reports suggesting that the RhoA-ROCK axis plays a role in VEGF-mediated angiogenesis, whereas other work has shown opposite effects. To elucidate this conflicting data, we examined HUVEC and HCAEC after stable overexpression (lentiviral transduction) of constitutively active (G14V/Q63L), dominant-negative (T19N), or wild-type RhoA using a variety of in vitro angiogenesis assays (proliferation, migration, tube formation, angiogenic sprouting, endothelial cell viability) and a HUVEC xenograft assay in immune incompetent NSGTM mice in vivo. We observed that expression of active as well as wild-type RhoA but not expression of dominant-negative RhoA significantly increased endothelial cell death as well as inhibited endothelial cell proliferation, migration, tube formation and angiogenic sprouting of endothelial cells in vitro and reduced HUVEC-related angiogenesis in vivo. Inhibition of RhoA by C3 transferase antagonized inhibitory RhoA effects and strongly enhanced VEGF-induced angiogenic sprouting in control-treated cells. In contrast, inhibition of RhoA effectors ROCK1/2 and LIMK1/2 had no significant effect on RhoA-related effects, but again increased angiogenic sprouting and migration of control-treated cells. In line with these data, VEGF did not activate RhoA in HUVEC as measured by a FRET-based biosensor. Furthermore, global transcriptome and subsequent bioinformatic gene ontology (GO) enrichment analyses revealed that constitutively active RhoA induces a differentially expressed gene pattern that is enriched for GO biological process terms such as mitotic nuclear division, cell proliferation, cell motility and cell adhesion and includes a significant decrease in VEGFR-2 and NOS3 expression. Thus, our data demonstrate that increased RhoA activity has the potential to trigger endothelial dysfunction and anti-angiogenic effects independently of its well-characterized downstream effectors ROCK and LIMK.

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RhoA wild-type allele loss unleashes the cancer driver function of RhoA E40Q

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