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Background <p>Resistance 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.</p> Methods <p>We 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 <i>TGFB2</i> expression and plasma TGF-β2 levels in HNSCC patient cohorts.</p> Results <p>Cetuximab-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 <i>TGFB2</i> expression and circulating TGF-β2 levels were associated with metabolic reprogramming and poorer clinical outcomes following cetuximab therapy.</p> Conclusions <p>Our 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.</p> Graphical Abstract <p></p>

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Reciprocal signaling-metabolic crosstalk between fibroblasts and tumor cells drives cetuximab tolerance in head and neck cancers

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月24日

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  • Engy Vigneron,
  • Julie Vignau,
  • Olivier Lowyck,
  • Valentin Van den bossche,
  • Jérôme Ambroise,
  • Yann Kieffer,
  • Fatima Mechta-Grigoriou,
  • Isabella Rizzi,
  • Maria Virginia Giolito,
  • Manon Desgres,
  • Hannah Zaryouh,
  • An Wouters,
  • Antonella Mendola,
  • Hajar Dahou,
  • Marine Leclerc,
  • Romain Boidot,
  • Aurélien Warnant,
  • Yvan Larondelle,
  • Olivier Feron,
  • Jean-Pascal Machiels,
  • Sandra Schmitz,
  • Cyril Corbet

摘要

Background

Resistance 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.

Methods

We 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.

Results

Cetuximab-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.

Conclusions

Our 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.

Graphical Abstract