establishment-histological-analysis-esophageal-organoids-modeling

Establishment and Histological Analysis of Esophageal Organoids Modeling the Progression from Normal to Cancerous Tissues

Organoids have emerged as a pivotal tool for advancing the understanding of tumorigenesis and cancer therapy. By generating human organoid models ...

Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC)

Chinese Academy of Medical Sciences and Peking Union Medical College

Chemotherapy remains the first-line treatment for advanced esophageal cancer. However, durable benefits are achieved by only a limited subset of individuals due to the elusive chemoresistance. Here, we utilize patient-derived xenografts (PDXs) from esophageal squamous-cell carcinoma to investigate chemoresistance mechanisms in preclinical settings. We observe that activated cancer-associated fibroblasts (CAFs) are enriched in the tumor microenvironment of PDXs resistant to chemotherapy. Mechanistically, we reveal that cancer-cell-derived S100A8 triggers the intracellular RhoA-ROCK-MLC2-MRTF-A pathway by binding to the CD147 receptor of CAFs, inducing CAF polarization and leading to chemoresistance. Therapeutically, we demonstrate that blocking the S100A8-CD147 pathway can improve chemotherapy efficiency. Prognostically, we found the S100A8 levels in peripheral blood can serve as an indicator of chemotherapy responsiveness. Collectively, our study offers a comprehensive understanding of the molecular mechanisms underlying chemoresistance in esophageal cancer and highlights the potential value of S100A8 in the clinical management of esophageal cancer.

Alarmin S100A8 imparts chemoresistance of esophageal cancer by reprogramming cancer-associated fibroblasts.

Cancer-associated fibroblasts (CAF) contribute to cancer initiation and progression and play a pivotal role in therapeutic response and patient prognosis. CAFs exhibit functional and phenotypic heterogeneity, highlighting the need to clarify the specific subtypes of CAFs to facilitate the development of targeted therapies against protumorigenic CAFs. In this study, using single-cell RNA sequencing on patient samples of esophageal squamous cell carcinoma (ESCC), we identified a CAF subcluster associated with tumor stemness that was enriched in genes associated with hypoxia and senescence. The CAF subpopulation, termed as hypoxia-induced senescent fibroblasts (hsCAF), displayed high secretion of insulin-like growth factor 1 (IGF1). The hsCAFs inhibited AMP-activated protein kinase (AMPK) activity in cancer cells via IGF1 to promote tumor stemness. The formation of hsCAFs was induced by the synergetic effect of hypoxia and cancer cells. Activation of nuclear factor erythroid 2-related factor 2 (NRF2) in cancer cells under hypoxia drove IL1α production to trigger CAF senescence and IGF1 secretion via nuclear factor I A. Knockout of IGF1 in CAFs or nuclear factor erythroid 2-related factor 2 in ESCC cells suppressed the tumor growth and chemotherapy resistance induced by CAFs in vivo. Importantly, patients with high proportions of hsCAFs showed poor survival and a worse response to chemotherapy. In summary, these findings identify a hsCAF subpopulation generated by interplay between cancer cells and CAFs under hypoxic conditions that promotes ESCC stemness and reveal targeting hsCAFs as an effective therapeutic strategy against chemotherapy-resistant ESCC. Significance: A hypoxic microenvironment and cancer cells cooperate to induce a senescent fibroblast subset that supports tumor stemness, suggesting that targeting this cancer-associated fibroblast subpopulation is a potential therapeutic strategy to overcome chemoresistance.

Article	Year
Alarmin S100A8 imparts chemoresistance of esophageal cancer by reprogramming cancer-associated fibroblasts. Cell reports. Medicine\| PubMed ID: 38776909	2024
Hypoxia-Induced Senescent Fibroblasts Secrete IGF1 to Promote Cancer Stemness in Esophageal Squamous Cell Carcinoma. Cancer research\| PubMed ID: 39661488	2025

Rucheng Liu

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