Adult interfollicular tumour-initiating cells are reprogrammed into an embryonic hair follicle progenitor-like fate during basal cell carcinoma initiation

Abstract

Basal cell carcinoma, the most frequent human skin cancer, arises from activating hedgehog (HH) pathway mutations; however, little is known about the temporal changes that occur in tumour-initiating cells from the first oncogenic hit to the development of invasive cancer. Using an inducible mouse model enabling the expression of a constitutively active Smoothened mutant (SmoM2) in the adult epidermis, we carried out transcriptional profiling of SmoM2-expressing cells at different times during cancer initiation. We found that tumour-initiating cells are massively reprogrammed into a fate resembling that of embryonic hair follicle progenitors (EHFPs). Wnt/ β-catenin signalling was very rapidly activated following SmoM2 expression in adult epidermis and coincided with the expression of EHFP markers. Deletion of β-catenin in adult SmoM2-expressing cells prevents EHFP reprogramming and tumour initiation. Finally, human basal cell carcinomas also express genes of the Wnt signalling and EHFP signatures.

Roles for Hedgehog signaling in adult organ homeostasis and repair

“…SMO gain-of-function and PTCH1 loss-of-function mutations give rise to BCC-like lesions when induced either in mouse interfollicular epidermis, or in hair follicle stem cells that move into the interfollicular skin after wounding (Kasper et al, 2011;Wong and Reiter, 2011;Youssef et al, 2012Youssef et al, , 2010. Hence, it is likely that two different stem cells can function as tumor-initiating cells for BCC.…”

“…Hence, it is likely that two different stem cells can function as tumor-initiating cells for BCC. Transcriptional profiling of tumor-initiating cells in the interfollicular epidermis has revealed that the tumorigenic cells assume an identity similar to that of embryonic hair follicle progenitor cells (Youssef et al, 2012). Furthermore, continuous GLI2-dependent SHH signaling appears to be required for the full establishment of BCC (Hutchin et al, 2005).…”

Patched Receptors Sense, Interpret, and Establish an Epidermal Hedgehog Signaling Gradient

“…A number of studies have been directed at dissecting the cellular origin of BCC, whereby Hh signalling activity has been activated in specific epidermal and HF stem/progenitor cell compartments. Despite these studies, the BCCinitiating cell compartment remains controversial and consensus has been difficult to attain with some studies reporting BCC formation following Hh activation in a variety of HF stem cell compartments (Grachtchouk et al, 2011;Kasper et al, 2011;Peterson et al, 2015;Wang et al, 2011), and others indicating BCC potential from IFE structures (Adolphe et al, 2006;Grachtchouk et al, 2011;Villani et al, 2010;Wong and Reiter, 2011;Youssef et al, 2012;Youssef et al, 2010) M A N U S C R I P T…”

WNT Signaling in Cutaneous Squamous Cell Carcinoma: A Future Treatment Strategy?

“…Unsurprisingly then, the WNT signaling network is also emerging as a dominant regulator in the development and progression of more common NMSCs too. In BCC, Hedgehog signaling up-regulates WNT/β-catenin activity (Yang, et al 2008), particularly at the leading edge of invasive tumours (Youssef, et al 2012) and stromally-derived WNT5A (signaling through the WNT/Ca 2+ pathway) causes BCC tumours to differentiate and regress (Nitzki, et al 2010).…”

“…The role of WNT signaling in a number of non-melanoma skin cancers (NMSCs) including BCC (El-Bahrawy, et al 2003;Salto-Tellez, et al 2006;Yang, et al 2008;Youssef, et al 2012) is already defined, however evidence is also emerging for a role in the development and progression of cSCC too. Here we examine this evidence and investigate the possibility of WNT inhibitors as a novel therapeutic opportunity for disease management of cSCC.…”