Cancer-associated fibroblasts (CAFs) 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 pro-tumorigenic CAFs. Here, 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 (hsCAFs), 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 interleukin-1 alpha (IL-1α) production to trigger CAF senescence and IGF1 secretion via nuclear factor I A (NFIA). Knockout of IGF1 in CAFs or NRF2 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.

中文翻译：

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缺氧诱导的衰老成纤维细胞分泌 IGF1 以促进食管鳞状细胞癌的癌症干性


癌症相关成纤维细胞 （CAFs） 有助于癌症的发生和进展，并在治疗反应和患者预后中起关键作用。CAFs 表现出功能和表型异质性，突出了阐明 CAFs 的特定亚型以促进针对促肿瘤 CAFs 的靶向疗法开发的必要性。在这里，对食管鳞状细胞癌 （ESCC） 患者样本进行单细胞 RNA 测序，我们确定了一个与肿瘤干性相关的 CAF 亚簇，该亚簇富含与缺氧和衰老相关的基因。CAF 亚群，称为缺氧诱导的衰老成纤维细胞 （hsCAF），表现出胰岛素样生长因子 1 （IGF1） 的高分泌。hsCAFs 通过 IGF1 抑制癌细胞中 AMP 活化蛋白激酶 （AMPK） 活性，促进肿瘤干性。hsCAFs 的形成是由缺氧和癌细胞的协同作用诱导的。在缺氧条件下，癌细胞中核因子红细胞 2 相关因子 2 （NRF2） 的激活驱动白细胞介素 1 α （IL-1α） 的产生，从而通过核因子 I A （NFIA） 触发 CAF 衰老和 IGF1 分泌。敲除 CAFs 中的 IGF1 或 ESCC 细胞中的 NRF2 抑制了 CAFs 在体内诱导的肿瘤生长和化疗耐药。重要的是，hsCAFs 比例高的患者生存率差，对化疗的反应更差。总之，这些发现确定了在缺氧条件下癌细胞和 CAFs 相互作用产生的 hsCAF 亚群，该亚群促进了 ESCC 干性，并揭示了靶向 hsCAFs 作为针对化疗耐药 ESCC 的有效治疗策略。