Spreading of Isolated Ptch Mutant Basal Cell Carcinoma Precursors Is Physiologically Suppressed and Counteracts Tumor Formation in Mice

Abstract

Basal cell carcinoma (BCC) originate from Hedgehog/Patched signaling-activated epidermal stem cells. However, the chemically induced tumorigenesis of mice with a CD4Cre-mediated biallelic loss of the Hedgehog signaling repressor Patched also induces BCC formation. Here, we identified the cellular origin of CD4Cre-targeted BCC progenitors as rare Keratin 5+ epidermal cells and show that wildtype Patched offspring of these cells spread over the hair follicle/skin complex with increasing mouse age. Intriguingly, Patched mutant counterparts are undetectable in age-matched untreated skin but are getting traceable upon applying the chemical tumorigenesis protocol. Together, our data show that biallelic Patched depletion in rare Keratin 5+ epidermal cells is not sufficient to drive BCC development, because the spread of these cells is physiologically suppressed. However, bypassing the repression of Patched mutant cells, e.g., by exogenous stimuli, leads to an accumulation of BCC precursor cells and, finally, to tumor development.

Basal cell carcinomas acquire secondary mutations to overcome dormancy and progress from microscopic to macroscopic disease

“…In mice, the absence of macroscopic BCCs has been a major shortcoming of both the conditional Ptch1 -deletion and SmoM2 -overexpression models, confirming that tumors do not progress, regardless of how upstream Hh signaling becomes activated or which Cre driver is utilized ( Brandes et al, 2020 ; Grachtchouk et al, 2003 ; Kasper et al, 2011 ; Mao et al, 2006 ; Peterson et al, 2015 ; Wang et al, 2017 ; Youssef et al, 2010 ). Indeed, previous studies have shown that nascent BCC-like tumors induced by non-targeted Ptch1 deletion similarly regress due to macrophage-induced tumor differentiation ( Nitzki et al, 2010 ).…”