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

• Published in: Cell stem cell 2017-11, Vol.21 (5), p.650-664.e8
• Main Authors: Brown, Jessie A., Yonekubo, Yoshiya, Hanson, Nicole, Sastre-Perona, Ana, Basin, Alice, Rytlewski, Julie A., Dolgalev, Igor, Meehan, Shane, Tsirigos, Aristotelis, Beronja, Slobodan, Schober, Markus
• Format: Article
• Language: English
• Subjects: Animals; cancer stem cells; Carcinoma, Squamous Cell - genetics; Carcinoma, Squamous Cell - pathology; cell cycle; Cell Cycle - drug effects; Cell Line, Tumor; chemotherapy; Chromatin - metabolism; Disease Progression; Drug Resistance, Neoplasm - drug effects; Gene Expression Profiling; Gene Expression Regulation, Neoplastic - drug effects; Head and Neck Neoplasms - genetics; Head and Neck Neoplasms - pathology; Humans; Mice; quiescence; resistance; Signal Transduction - drug effects; skin; Smad Proteins - metabolism; squamous cell carcinoma; Squamous Cell Carcinoma of Head and Neck; Staining and Labeling; TGF-β; Transforming Growth Factor beta - pharmacology; tumor heterogeneity; tumor propagating cells
• ISSN: 1934-5909; 1875-9777
• DOI: 10.1016/j.stem.2017.10.001

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 p21CIP 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. [Display omitted] •Functional identification of quiescent, therapy-resistant TPCs in intact SCCs•Transcriptional signatures define quiescent and proliferative states of TPCs•Smad2-dependent transcripts elicit a reversible G1 arrest independent of p21CIP•TGF-β inhibition prevents quiescence-mediated chemotherapy resistance in SCCs 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.