168 De novo PITX1 expression controls bi-stable network motifs to govern self-renewal in squamous cell carcinoma

Abstract

Squamous cell carcinoma (SCC) growth is governed by tumor propagating progenitor cells (TPCs) that self-renew and differentiate into SCC cells without proliferative potential. The molecular mechanisms controlling this fate choice within these tumors are still elusive. Here we identify PITX1 as a fate determining transcription factor in mouse and human SCCs. PITX1 co-localizes with SOX2 and TRP63 in nuclei of TPCs, but it is not detected in differentiated SCC cells. Conditional gene targeting combined with ChIP-sequencing and transcriptomics reveals PITX1 cooperates with SOX2 and TRP63 to sustain a SCC specific transcriptional feed forward circuit that maintain TPC-renewal, while they also inhibit Klf4transcription and KLF4 dependent squamous differentiation. Conversely, KLF4 represses PITX1, SOX2 and TRP63 expression to prevent their expansion into supra-basal layers. This bi-stable multi-input network motif provides a molecular framework that explains self-renewal, aberrant differentiation and SCC growth in mice and humans, revealing new clues for differentiation stimulating therapies for SCCs.