Figure 1. Bi-stable self-renewal and differentiation networks define SCC growth. (A) Stratified epithelia like epidermis express TP63 in proliferative basal, and KLF4 in post-mitotic, supra-basal cell layers. SCC formation coincides with de novo Pitx1 and Sox2 expression. PITX1 and SOX2 co-localize with TP63 in nuclei of basal TPCs, until their expression fades and KLF4 strengthens allowing TPCs to differentiate into SCC cells without proliferative potential. (B) The fate choice between TPC self-renewal and differentiation is governed by a bi-stable transcriptional network where PITX1, SOX2, and TP63 enhance each other’s transcription to drive self-renewal as they repress and are repressed by a KLF4 dependent squamous differentiation program.