| First Author | Oshimori N | Year | 2015 |
| Journal | Cell | Volume | 160 |
| Issue | 5 | Pages | 963-76 |
| PubMed ID | 25723170 | Mgi Jnum | J:222878 |
| Mgi Id | MGI:5645852 | Doi | 10.1016/j.cell.2015.01.043 |
| Citation | Oshimori N, et al. (2015) TGF-beta promotes heterogeneity and drug resistance in squamous cell carcinoma. Cell 160(5):963-76 |
| abstractText | Subsets of long-lived, tumor-initiating stem cells often escape cancer therapies. However, sources and mechanisms that generate tumor heterogeneity and drug-resistant cell population are still unfolding. Here, we devise a functional reporter system to lineage trace and/or genetic ablate signaling in TGF-beta-activated squamous cell carcinoma stem cells (SCC-SCs). Dissecting TGF-beta's impact on malignant progression, we demonstrate that TGF-beta concentrating near tumor-vasculature generates heterogeneity in TGF-beta signaling at tumor-stroma interface and bestows slower-cycling properties to neighboring SCC-SCs. While non-responding progenies proliferate faster and accelerate tumor growth, TGF-beta-responding progenies invade, aberrantly differentiate, and affect gene expression. Intriguingly, TGF-beta-responding SCC-SCs show increased protection against anti-cancer drugs, but slower-cycling alone does not confer survival. Rather, TGF-beta transcriptionally activates p21, which stabilizes NRF2, thereby markedly enhancing glutathione metabolism and diminishing effectiveness of anti-cancer therapeutics. Together, these findings establish a surprising non-genetic paradigm for TGF-beta signaling in fueling heterogeneity in SCC-SCs, tumor characteristics, and drug resistance. |
