Drug Vulnerabilities and Disease Prognosis Linked to the Stem Cell-Like Gene Expression Program Triggered by the RHO GTPase Activator VAV2 in Hyperplastic Keratinocytes and Head and Neck Cancer

Luis Francisco Lorenzo-Martín,Xosé R Bustelo,Mauricio Menacho-Márquez

doi:10.3390/cancers12092498

Abstract

We have recently shown that VAV2, a guanosine nucleotide exchange factor that catalyzes the stimulation step of RHO GTPases, is involved in a stem cell-like (SCL) regenerative proliferation program that is important for the development and subsequent maintenance of the tumorigenesis of both cutaneous (cSCC) and head and neck squamous cell carcinomas (hnSCC). In line with this, we have observed that the levels of the VAV2 mRNA and VAV2-regulated gene signatures are associated with poor prognosis in the case of human papillomavirus-negative hnSCC patients. These results suggest that the SCL program elicited by VAV2 in those cells can harbor therapeutically actionable downstream targets. We have addressed this issue using a combination of both in silico and wet-lab approaches. Here, we show that the VAV2-regulated SCL program does harbor a number of cell cycle- and signaling-related kinases that are essential for the viability of undifferentiated keratinocytes and hnSCC patient-derived cells endowed with high levels of VAV2 activity. Our results also show that the VAV2-regulated SCL gene signature is associated with poor hnSCC patient prognosis. Collectively, these data underscore the critical role of this VAV2-regulated SCL program for the viability of both preneoplastic and fully transformed keratinocytes.

Highlights

One of the hallmarks of cancer cells is their ability to hijack molecular programs that are usually restricted to progenitor and stem cells [1]
In order to understand the role of upregulated VAV2 signaling in epithelial cells, we recently utilized a catalytic gain-of-function knock-in mouse strain that expresses a mutant version of the mouse
In keeping with the microarray and functional annotation data, we found that the highest-ranking group of drugs predicted to be effective against this Vav2Onc -driven transcriptional program includes inhibitors for cell cycle-associated proteins, receptor protein tyrosine kinases (RTKs), phosphatidylinositol 3-kinase (PI3K), and mitogen-activated protein kinases (MAPKs) (Figure 2F)

Summary

Introduction

One of the hallmarks of cancer cells is their ability to hijack molecular programs that are usually restricted to progenitor and stem cells [1]. Doing so without negatively affecting the physiological function of healthy stem cells remains a major concern when considering clinical applications [1] As it occurs in the case of other cancer-associated pathobiological programs, the eventual success of such therapies would rely on the degree of addiction that tumor cells might develop for the targeted processes when compared to the healthy counterparts [4]. In this context, the identification of biomarkers able to predict tumor cell dependency towards specific stem cell-associated molecular pathways holds great translational potential

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Conclusion