Stromal cells in the tumor microenvironment regulate the immune landscape and tumor progression. Yet, the ontogeny and heterogeneity of reactive stromal cells within tumors is not well understood. Carcinoma-associated fibroblasts exhibiting an inflammatory phenotype (iCAFs) have been identified within multiple cancers; however, mechanisms that lead to their recruitment and differentiation also remain undefined. Targeting these mechanisms therapeutically may be important in managing cancer progression. Here, we identify the ELF3 transcription factor as the canonical mediator of IL-1α-induced differentiation of prostate mesenchymal stem cells to an iCAF phenotype, typical of the tumor microenvironment. Furthermore, IL-1α-induced iCAFs were subsequently refractive to TGF-β1 induced trans-differentiation to a myofibroblast phenotype (myCAF), another key carcinoma-associated fibroblast subtype typical of reactive stroma in cancer. Restricted trans-differentiation was associated with phosphorylation of the YAP protein, indicating that interplay between ELF3 action and activation of the Hippo pathway are critical for restricting trans-differentiation of iCAFs. Together, these data show that the IL-1α/ELF3/YAP pathways are coordinate for regulating inflammatory carcinoma-associated fibroblast differentiation.

中文翻译：

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ELF3 介导 IL-1α 诱导的间充质干细胞向炎性 iCAF 的分化

肿瘤微环境中的基质细胞调节免疫景观和肿瘤进展。然而，肿瘤内反应性基质细胞的个体发育和异质性尚不清楚。已在多种癌症中鉴定出表现出炎症表型 (iCAF) 的癌相关成纤维细胞；然而，导致他们招募和分化的机制也仍未明确。在治疗上针对这些机制可能对控制癌症进展很重要。在这里，我们将 ELF3 转录因子鉴定为 IL-1α 诱导的前列腺间充质干细胞分化为 iCAF 表型（典型的肿瘤微环境）的典型介质。此外，IL-1α 诱导的 iCAF 随后折射为 TGF-β1 诱导的转分化为肌成纤维细胞表型 (myCAF)，另一种关键的癌相关成纤维细胞亚型，典型的癌症反应性基质。限制性转分化与 YAP 蛋白的磷酸化相关，表明 ELF3 作用与 Hippo 通路激活之间的相互作用对于限制 iCAF 的转分化至关重要。总之，这些数据表明 IL-1α/ELF3/YAP 通路协调调节炎性癌相关的成纤维细胞分化。