TGF-β promotes heterogeneity and drug resistance in squamous cell carcinoma

Area of Science:

• Oncology
• Cancer Stem Cell Biology
• Molecular Signaling

Background:

• Long-lived cancer stem cells evade therapies, contributing to tumor recurrence.
• Mechanisms generating tumor heterogeneity and drug resistance remain incompletely understood.

Purpose of the Study:

• To investigate the role of transforming growth factor-beta (TGF-β) in driving heterogeneity and drug resistance in squamous cell carcinoma stem cells (SCC-SCs).
• To elucidate the signaling pathways and cellular behaviors influenced by TGF-β in SCC-SCs.

Main Methods:

• Development of a functional reporter system for lineage tracing and genetic ablation of TGF-β signaling in SCC-SCs.
• Analysis of TGF-β signaling gradients at the tumor-stroma interface.
• Assessment of cell-cycle properties, invasion, differentiation, and drug sensitivity in TGF-β-responding and non-responding SCC-SCs.
• Investigation of molecular mechanisms, including p21 and NRF2 stabilization, and glutathione metabolism.

Main Results:

• TGF-β signaling heterogeneity at the tumor-stroma interface promotes slower cycling in neighboring SCC-SCs.
• TGF-β-responding SCC-SCs exhibit increased invasion, aberrant differentiation, and enhanced resistance to anti-cancer drugs.
• TGF-β upregulates p21, which stabilizes NRF2, leading to increased glutathione metabolism and reduced drug efficacy.
• Slower cell cycling alone does not confer drug resistance; the TGF-β-induced molecular pathway is critical.

Conclusions:

• TGF-β signaling establishes a non-genetic mechanism driving heterogeneity and drug resistance in SCC-SCs.
• Targeting the TGF-β/p21/NRF2 axis may overcome drug resistance in squamous cell carcinoma.
• Understanding these pathways is crucial for developing more effective cancer therapies.