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.

中文翻译：

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TGF-β诱导的沉默介导鳞状细胞癌中肿瘤增殖细胞的化学耐药性。

鳞状细胞癌（SCC）是由肿瘤传播的癌细胞（TPC）维持的异质性肿瘤。SCC经常通过未知的机制抵抗化学疗法。在这里，我们将基于H2B-GFP的脉冲追踪与细胞表面标记相结合，以区分SCC中增殖性TPC的静态与静止状态。我们发现，静止的TPC抵抗DNA损伤，并显示出对化疗反应的致瘤潜力，而增殖性TPC则发生凋亡。静止性受TGF-β/ SMAD信号传导调节，该信号传导直接调节细胞周期基因转录，以控制可逆性G1细胞周期阻滞，而与p21 ^CIP无关功能。实际上，遗传或药理学上的TGF-β抑制作用会增加TPC对化学疗法的敏感性，因为它可以防止进入静止状态。这些发现提供了直接的证据，表明TPC可以可逆地进入静止的化学抗性状态，从而突显了需要采用组合方法来改善对化疗耐药的SCC的治疗。