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Chemoresistant fibroblasts dictate neoadjuvant chemotherapeutic response of head and neck cancer via TGFα-EGFR paracrine signaling. | LitMetric

Chemoresistant fibroblasts dictate neoadjuvant chemotherapeutic response of head and neck cancer via TGFα-EGFR paracrine signaling.

NPJ Precis Oncol

Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA medicine, Sun Yat-sen Memorial Hospital, State Key Laboratory of Oncology in South China, Sun Yat-sen University, Guangzhou, 510120, China.

Published: October 2023

Conventional chemotherapy targets malignant cells without evaluating counter protection from the tumor microenvironment that often causes treatment failure. Herein, we establish chemoresistant fibroblasts (rCAFs) as regulators of neoadjuvant chemotherapeutic (NACT) response in head and neck squamous cell carcinoma (HNSCC). Clinically, high expression of CAF-related gene signature correlates with worse prognosis and chemotherapeutic response in multiple cancers, while the population of CAFs in the residual tumors of chemoresistant HNSCC patients remains unchanged after NACT treatment, compared to chemosensitive patients. Using a murine cancer model or patient-derived organoid, and primary CAFs isolated from chemo-sensitive (sCAFs) or -resistant patients, we show that rCAFs, but not sCAFs, are resistant to chemotherapy-induced apoptosis while reducing HNSCC cell chemosensitivity via paracrine signals. Combined multi-omics and biochemical analyses indicate an elevated PI3K/AKT/p65 driven cell survival and cytokine production in rCAFs, while rCAF-secreted TGFα promotes cancer cell chemoresistance by activating EGFR/Src/STAT3 survival signaling axis. Treatment with anti-EGFR cetuximab restores the chemosensitivity of tumors derived from co-injection of cancer cells and rCAFs in vivo, while the serum level of TGFα determines NACT response in HNSCC patients. Overall, our findings uncover a novel insight whereby the crosstalk between tumor cell and rCAF determines chemotherapeutic response and prognosis in cancer patients.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10567732PMC
http://dx.doi.org/10.1038/s41698-023-00460-2DOI Listing

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