YAP-TEAD signaling promotes basal cell carcinoma development via a c-JUN/AP1 axis.

Raffaele A Calogero,Antonella FM Dost,Karin Schlegelmilch,Dejan Maglic,Riccardo Panero,Michael T Dill,Fernando D Camargo

doi:10.15252/embj.201798642

Abstract

The mammalian Hippo signaling pathway, through its effectors YAP and TAZ, coerces epithelial progenitor cell expansion for appropriate tissue development or regeneration upon damage. Its ability to drive rapid tissue growth explains why many oncogenic events frequently exploit this pathway to promote cancer phenotypes. Indeed, several tumor types including basal cell carcinoma (BCC) show genetic aberrations in the Hippo (or YAP/TAZ) regulators. Here, we uncover that while YAP is dispensable for homeostatic epidermal regeneration, it is required for BCC development. Our clonal analyses further demonstrate that the few emerging Yap-null dysplasia have lower fitness and thus are diminished as they progress to invasive BCC Mechanistically, YAP depletion in BCC tumors leads to effective impairment of the JNK-JUN signaling, a well-established tumor-driving cascade. Importantly, inthis context, YAP does not influence canonical Wnt or Hedgehog signaling. Overall, we reveal Hippo signaling as an independent promoter of BCCpathogenesis and thereby a viable target for drug-resistant BCC.

Highlights

Discovered in Drosophila, the mammalian Hippo signaling pathway is a central modulator of progenitor cell state necessary for proper epithelial tissue regeneration
By using human tumor samples, genetically engineered mouse models, and in vitro cell lines, our study provides substantial evidence that: (i) YAP is dispensable for homeostatic epidermal regeneration; (ii) YAP activity is enriched in the basal tumor cells of basal cell carcinoma-like (BCC); (iii) YAP-TEA domain (TEAD) interaction is required for BCC initiation and tumor maintenance; and (iv) YAP potentiates c-JUN activity to drive BCC growth
The vast majority of BCC are curable with resection, vismodegib (SMO inhibitor) therapy, or a combination of both, the projected increase in BCC incidence over coming decades will result in a surge of advanced and vismodegib-resistant cases (Danhof et al, 2018)

Summary

Introduction

Discovered in Drosophila, the mammalian Hippo signaling pathway is a central modulator of progenitor cell state necessary for proper epithelial tissue regeneration. Coordinated YAP/TAZ-TEAD interaction and resulting gene signature is vital for embryonic tissue development, as any perturbation in their function results in the depletion of progenitor cell pool and failed organogenesis (Varelas, 2014). The robust propensity of activated YAP and TAZ to enhance the progenitor cell state phenotype (i.e., self-renewal, epithelial–mesenchymal transition, proliferation, and survival) in epithelial cells is believed to be the reason why cancer cells frequently hijack the Hippo pathway during tumorigenesis (Harvey et al, 2013). Short-term epidermal YAP overexpression induces the expansion of undifferentiated/progenitor cells in the interfollicular epidermis (IFE), skin thickening, and development of basal cell carcinoma-like (BCC) lesions (Schlegelmilch et al, 2011; Silvis et al, 2011; Zhang et al, 2011; Akladios et al, 2017)

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