ΔNp63/p73 drive metastatic colonization by controlling a regenerative epithelial stem cell program in quasi-mesenchymal cancer stem cells.

Autor:	Lambert AW; Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA., Fiore C; Syros Pharmaceuticals, Cambridge, MA 02140, USA., Chutake Y; Syros Pharmaceuticals, Cambridge, MA 02140, USA., Verhaar ER; Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA., Strasser PC; Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA., Chen MW; Syros Pharmaceuticals, Cambridge, MA 02140, USA., Farouq D; Syros Pharmaceuticals, Cambridge, MA 02140, USA., Das S; Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA., Li X; Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA., Eaton EN; Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA., Zhang Y; Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China., Liu Donaher J; Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA., Engstrom I; Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA., Reinhardt F; Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA., Yuan B; Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA., Gupta S; Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA., Wollison B; Syros Pharmaceuticals, Cambridge, MA 02140, USA., Eaton M; Syros Pharmaceuticals, Cambridge, MA 02140, USA., Bierie B; Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA., Carulli J; Syros Pharmaceuticals, Cambridge, MA 02140, USA., Olson ER; Syros Pharmaceuticals, Cambridge, MA 02140, USA., Guenther MG; Syros Pharmaceuticals, Cambridge, MA 02140, USA., Weinberg RA; Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; MIT Ludwig Center for Molecular Oncology, Cambridge, MA 02139, USA. Electronic address: weinberg@wi.mit.edu.
Jazyk:	angličtina
Zdroj:	Developmental cell [Dev Cell] 2022 Dec 19; Vol. 57 (24), pp. 2714-2730.e8.
DOI:	10.1016/j.devcel.2022.11.015
Abstrakt:	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 β4 (ITGB4) to isolate highly enriched populations of human breast CSCs, and we identified the gene regulatory network operating in ITGB4 + CSCs. Specifically, we identified ΔNp63 and p73, the latter of which transactivates ΔNp63, as centrally important transcriptional regulators of quasi-mesenchymal CSCs that reside in an intermediate EMT state. We found that the transcriptional program controlled by ΔNp63 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. Competing Interests: Declaration of interests R.A.W. has a consulting agreement with Verastem Inc., and he has held shares of this company. C.F., Y.C., M.W.C., B.W., M.E., D.F., J.C., E.R.O., and M.G.G. were or are employees of Syros Pharmaceuticals. (Copyright © 2022 Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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