ArticleJournal of experimental & clinical cancer research : CR2026
Reciprocal signaling-metabolic crosstalk between fibroblasts and tumor cells drives cetuximab tolerance in head and neck cancers.
Article in Journal of experimental & clinical cancer research : CR, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
backgroundResistance to EGFR-targeted therapies, including cetuximab, remains a major barrier to effective treatment of head and neck squamous cell carcinoma (HNSCC). Lipid metabolism reprogramming, TGFβ signaling, and cancer-associated fibroblast (CAF) activation have each been linked to cetuximab resistance, but how these processes mechanistically converge remains unclear.
methodsWe integrated transcriptomic, metabolic, and biochemical assays in HNSCC cell lines, co-culture systems with matched patient-derived non tumoral fibroblasts and CAFs, patient-derived organoids (PDOs), and patient-derived xenografts (PDXs) to characterize tumor-stroma interactions during cetuximab treatment. Fluorescence-based fatty acid (FA) tracing and lipidomic analyses were used to assess FA flux. Functional relevance was tested through genetic and pharmacologic inhibition of TGF-β2 signaling and FA transfer. Clinical relevance was assessed by analyzing TGFB2 expression and plasma TGF-β2 levels in HNSCC patient cohorts.
resultsCetuximab-treated HNSCC cells specifically upregulated and secreted TGF-β2, which induced two coordinated adaptive programs: (i) autocrine metabolic rewiring promoting FA uptake, oxidation, and storage in tumor cells, and (ii) paracrine activation of fibroblasts toward a myofibroblastic, lipid-secreting phenotype. These TGFβ2-activated CAFs supplied FA that sustained oxidative metabolism and preserved EGFR/MAPK signaling in tumor cells, establishing a reciprocal feedback loop that maintained a reversible drug-tolerant state. Disrupting either TGF-β2 signaling or FA transfer abrogated this circuit and restored cetuximab sensitivity in HNSCC cells, spheroids, and PDOs. In PDX models, TGF-β2 inhibition delayed tumor regrowth following cetuximab treatment. Elevated TGFB2 expression and circulating TGF-β2 levels were associated with metabolic reprogramming and poorer clinical outcomes following cetuximab therapy.
conclusionsOur findings define a tumor-stroma metabolic cooperation axis in which TGFβ2-driven lipid exchange sustains adaptive cetuximab tolerance in HNSCC. Targeting TGFβ2-mediated stromal reprogramming or FA transfer represents a promising strategy to delay or overcome resistance to EGFR-targeted therapies.
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