Rho exchange factors in the regulation of squamous cell stemness and carcinogenesis

Resumen

The squamous cell carcinoma (SCC) is a major cause of cancer mortality. The carcinogenesis of this tumor is linked to a series of molecular derangements that frequently features the deregulation of RHO GTPase signaling. However, the events and agents underpinning such deregulation are yet to be defined. RHO exchange factors (GEFs), the proteins that catalyze the activation of RHO GTPases, have been traditionally contemplated as potential protumorigenic players in this context, but their large numbers and the lack of appropriate models has precluded the elucidation of their true functions in cancer settings. To address this issue, in this thesis we have focused on VAV2 to spearhead the characterization of RHO GEFs as key mediators of tumorigenesis and, more importantly, as candidate targets for novel SCC-directed therapeutic approaches. Here we demonstrate that VAV2 becomes upregulated in cutaneous and head-and-neck SCCs, where it engages a transcriptional program involved in the induction of stem cell-like regenerative proliferation and undifferentiation. Significantly, we show that VAV2 activity predicts disease outcome and that its inhibition within specific catalytic thresholds provides antitumoral benefits without disturbing organismal homeostasis. This work also exposes non-oncogenic roles for this GEF in the physiological maintenance of the cutaneous squamous epithelium, where it regulates the abundance, activity and responsiveness of hair follicle stem cells through the control of their transcriptomic circuits. Lastly, by extending these studies to the whole family of RHO GEFs, our research shows that VAV2 belongs to a small collection of exchange factors with pivotal roles in either the promotion or impairment of SCC tumorigenesis-associated processes. Taken together, our findings unveil hitherto unknown regulators of SCC fitness whose activity can be harnessed to modulate tumor growth and malignancy.