TGF-β-Induced Quiescence Mediates Chemoresistance of Tumor-Propagating Cells in Squamous Cell Carcinoma

Publication date: 2 November 2017
Source:Cell Stem Cell, Volume 21, Issue 5
Author(s): Jessie A. Brown, Yoshiya Yonekubo, Nicole Hanson, Ana Sastre-Perona, Alice Basin, Julie A. Rytlewski, Igor Dolgalev, Shane Meehan, Aristotelis Tsirigos, Slobodan Beronja, Markus Schober
Squamous cell carcinomas (SCCs) are heterogeneous tumors sustained by tumor-propagating cancer cells (TPCs). SCCs frequently resist chemotherapy through still unknown mechanisms. Here, we combine H2B-GFP-based pulse-chasing with cell-surface markers to distinguish quiescent from proliferative TPCs within SCCs. We find that quiescent TPCs resist DNA damage and exhibit increased tumorigenic potential in response to chemotherapy, whereas proliferative TPCs undergo apoptosis. Quiescence is regulated by TGF-β/SMAD signaling, which directly regulates cell-cycle gene transcription to control a reversible G1 cell-cycle arrest, independent of p21^CIP function. Indeed, genetic or pharmacological TGF-β inhibition increases the susceptibility of TPCs to chemotherapy because it prevents entry into a quiescent state. These findings provide direct evidence that TPCs can reversibly enter a quiescent, chemoresistant state and thereby underscore the need for combinatorial approaches to improve treatment of chemotherapy-resistant SCCs.

Graphical abstract

Teaser

Heterogeneous tumors, such as squamous cell carcinomas, are often chemoresistant and comprise subpopulations of poorly characterized tumor-propagating cancer cells (TPCs). Brown et al. demonstrate that TPCs reversibly enter a quiescent, chemoresistant state and inhibiting TGF-β signaling can increase their susceptibility to chemotherapy by preventing cell-cycle withdrawal in tumors.


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