Abstract
Regenerative proliferation capacity and poor differentiation are histological features usually linked to poor prognosis in head and neck squamous cell carcinoma (hnSCC). However, the pathways that regulate them remain ill-characterized. Here, we show that those traits can be triggered by the RHO GTPase activator VAV2 in keratinocytes present in the skin and oral mucosa. VAV2 is also required to maintain those traits in hnSCC patient-derived cells. This function, which is both catalysis- and RHO GTPase-dependent, is mediated by c-Myc- and YAP/TAZ-dependent transcriptomal programs associated with regenerative proliferation and cell undifferentiation, respectively. High levels of VAV2 transcripts and VAV2-regulated gene signatures are both associated with poor hnSCC patient prognosis. These results unveil a druggable pathway linked to the malignancy of specific SCC subtypes.
Highlights
Regenerative proliferation capacity and poor differentiation are histological features usually linked to poor prognosis in head and neck squamous cell carcinoma
In favor of the connection of VAV2 with this type of tumors, work with human head and neck squamous cell carcinoma (hnSCC) cell lines has revealed that this guanosine nucleotide exchange factors (GEFs) is frequently tyrosine phosphorylated and involved in the stimulation of RAC1 downstream of the epidermal growth factor receptor (EGFR) in a significant number of the interrogated cell lines[11]
The use of catalytically deficient Vav[2] knock-in mice has demonstrated that the inhibition of the enzymatic activity of Vav[2] impairs both the papilloma and cSCC formation that are typically induced upon the topic administration of the carcinogen 7,12-dimethylbenz(a)anthracene (DMBA) either alone or in combination with the tumor promoter 12-Otetradecanoylphorbol-13-acetate (TPA)[11]
Summary
Regenerative proliferation capacity and poor differentiation are histological features usually linked to poor prognosis in head and neck squamous cell carcinoma (hnSCC). VAV2 is required to maintain those traits in hnSCC patient-derived cells This function, which is both catalysis- and RHO GTPase-dependent, is mediated by c-Myc- and YAP/TAZ-dependent transcriptomal programs associated with regenerative proliferation and cell undifferentiation, respectively. Cutaneous (cSCC) and hnSCCs develop from the stratified epithelia of the skin and the mucosal lining of the upper aerodigestive tract, respectively These tumors represent nowadays a clinical challenge due to increasing incidence worldwide, aggressiveness, poor prognosis, and limited efficacy of available therapeutic tools. We still have a poor understanding of the molecular and signaling programs that regulate these malignant traits Recent work in this area has revealed that nuclear factors such as AP1 and E2F family members, c-MYC, the YAP/ TAZ complex, TP63, and ACTL6A can trigger those processes[3,4,5,6,7,8]. Efforts at blocking RAC1 signaling pathways in tumors have failed so far due to the intrinsic undruggability of RHO GTPases and the unwanted side-effects of inhibitors for downstream elements such as the Pak family of serine/threonine kinases[10]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
