?Np63/p73 drive metastatic colonization by controlling a regenerative epithelial stem cell program in quasi-mesenchymal cancer stem cells

Cancer stem cells (CSCs) may serve as the cellular seeds of tumor recurrence and metastasis, and they can be generated via epithelial-mesenchymal transitions (EMTs). Isolating pure populations of CSCs is difficult because EMT programs generate multiple alternative cell states, and phenotypic plasticity permits frequent interconversions between these states. Here, we used cell-surface expression of integrin b4 (ITGB4) to isolate highly enriched populations of human breast CSCs, and we identified the gene regulatory network operating in ITGB4+ CSCs. Specifically, we identified DNp63 and p73, the latter of which transactivates DNp63, as centrally important transcriptional regulators of quasi-mesenchymal CSCs that reside in an intermediate EMT state. We found that the transcriptional program controlled by DNp63 in CSCs is largely distinct from the one that it orchestrates in normal basal mammary stem cells and, instead, it more closely resembles a regenerative epithelial stem cell response to wounding. Moreover, quasi-mesenchymal CSCs repurpose this program to drive metastatic colonization via autocrine EGFR signaling.

Automated summary

This study isolated highly enriched populations of human breast cancer stem cells (CSCs) using cell-surface expression of integrin b4 (ITGB4), and identified the gene regulatory network operating in ITGB4+ CSCs. The transcriptional program controlled by DNp63 in CSCs was found to be distinct from that in normal basal mammary stem cells, and instead resembled a regenerative epithelial stem cell response to wounding. Additionally, the quasi-mesenchymal CSCs repurpose this program to drive metastatic colonization via autocrine EGFR signaling.