Abstract
Perivascular TGFβ generates heterogeneity and confers cisplatin resistance in SCC stem cells.
Major finding: Perivascular TGFβ generates heterogeneity and confers cisplatin resistance in SCC stem cells.
Mechanism: TGFβ promotes drug resistance via p21–NRF2-mediated glutathione metabolism gene transcription.
Impact: TGFβ enhances the invasion and resistance of slow-cycling SCC stem cells to drive tumor recurrence.
Intratumor heterogeneity in biological processes such as proliferation, motility, and differentiation has been linked with therapeutic resistance and metastatic growth. Although changes in the genetic landscape have historically been thought to promote tumor cell diversity, nongenetic factors within the tumor or surrounding microenvironment may also drive functional heterogeneity. The TGFβ pathway plays a paradoxical role in the initiation and progression of squamous cell carcinoma (SCC), and SCC stem cell numbers increase in the absence of TGFβ signaling, suggesting that TGFβ signaling may contribute to heterogeneity in cycling kinetics and response to anticancer therapies in tumor-initiating cells. To monitor and track TGFβ signaling during SCC progression, Oshimori and colleagues designed an in vivo lentiviral TGFβ reporter system, which showed that TGFβ-responding stem cells localized at the tumor–stroma interface of HRAS-induced tumors in perivascular regions that displayed high stromal TGFβ ligand expression. In contrast to nonresponding cells with high cycling rates, TGFβ-responding SCC stem cells were slow-cycling, more invasive, and exhibited aberrant differentiation. In addition, TGFβ-responding stem cells were more resistant to cisplatin-induced DNA damage–mediated apoptosis in vitro, and promoted drug resistance and tumor recurrence in vivo. Transcriptional profiling of TGFβ-responsive stem cells revealed enrichment for genes bound by the nuclear factor, erythroid 2-like 2 (NFE2L2, also known as NRF2) transcription factor that are involved in glutathione metabolism and facilitate reactive oxygen species neutralization and cisplatin metabolism. Mechanistically, TGFβ activated NRF2-mediated transcription of antioxidant genes via p21-mediated NRF2 protein stabilization. Importantly, chemical or genetic inhibition of NRF2-stimulated glutathione metabolism sensitized TGFβ-responding stem cells to cisplatin, whereas NRF2 overexpression conferred cisplatin resistance in cells deficient in TGFβ signaling. Together, these results highlight a previously unrecognized nongenetic mechanism of drug resistance in SCC mediated by TGFβ-driven tumor cell heterogeneity.
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