PO.TB10.11 · 肿瘤生物学
解码乳腺癌中基质驱动炎症的新机制
Decoding new mechanisms of stromal-driven inflammation in breast cancer
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
癌症相关成纤维细胞（CAF）是乳腺肿瘤微环境（TME）中一个丰富的细胞群。肿瘤中存在多种CAF表型，其中炎症型（iCAF）的特征是白细胞介素6（IL-6）的高表达。缺氧促进iCAF表型，并与乳腺癌患者的不良预后相关。然而，缺氧暴露驱动iCAF程序的分子机制仍不明确。我们分析了暴露于缺氧的患者来源CAF的蛋白质组和分泌组的变化，并识别出一种富含亮氨酸重复的蛋白（LRRC）是上调最显著的蛋白之一。进一步分析表明，LRRC以HIF1alpha依赖性方式在转录水平上被缺氧诱导。组织学分析显示，LRRC在跨物种的CAF中独特表达，在人类和小鼠乳腺肿瘤中均是如此。乳腺癌患者的单细胞RNA测序进一步证实了LRRC的基质特异性。通过在CAF中的功能缺失方法，我们发现LRRC是IL-6的上游调节因子，而IL-6是癌症中病理性血管生成和炎症的关键驱动因素。值得注意的是，LRRC+ CAF激活了癌细胞和TME细胞中的STAT信号。支持在肿瘤中具有类似作用，在TCGA蛋白质组学数据中，LRRC高表达的乳腺癌患者的肿瘤中也观察到STAT磷酸化增加。因此，通过调节IL-6，LRRC可能作为乳腺癌病理性血管生成和炎症的驱动因素发挥作用。事实上，我们观察到LRRC促进内皮出芽性血管生成以及CAF和TME细胞中的炎症转录程序。提示LRRC具有促肿瘤作用，在TCGA数据集中，高水平的LRRC与乳腺癌患者的生存恶化相关。为了确定LRRC+ CAF对周围TME的影响，我们正在利用乳腺癌患者组织的空间蛋白质组学分析。总之，我们的发现将LRRC定位为乳腺癌炎症信号的核心调节因子。通过在IL-6上游发挥功能并驱动STAT的激活，LRRC成为将缺氧与iCAF表型及其促肿瘤功能联系起来的关键分子枢纽。发现助长乳腺癌炎症的微环境因素是该领域一个备受追求的里程碑，因为它可能带来旨在破坏基质驱动炎症和肿瘤进展的新型治疗干预措施的开发。
查看英文原文 English abstract
Cancer-associated fibroblasts (CAFs) are an abundant cell population of the breast tumor microenvironment (TME). Several CAF phenotypes exist in tumors, being the inflammatory type (iCAF) characterized by the high expression of interleukin 6 (IL-6). Hypoxia promotes the iCAF phenotype and is linked to poor prognosis of breast cancer patients. However, the molecular mechanism driving the iCAF program upon hypoxia exposure remains elusive. We analyzed the changes in the proteome and secretome of patient-derived CAFs exposed to hypoxia and identified a Leucine Rich Repeat Containing Protein (LRRC) as one of the most up-regulated proteins. Further analyses revealed that LRRC in induced by hypoxia at transcriptional level in a HIF1alpha-dependent manner. Histological analyses show that LRRC is uniquely expressed in CAFs across species, in both human and murine breast tumors. Stromal specificity of LRRC was further confirmed by single-cell RNA sequencing of breast cancer patients. Through loss-of-function approaches in CAFs we uncovered that LRRC is an upstream regulator of IL-6, a key driver of pathological angiogenesis and inflammation in cancer. Notably, LRRC + CAFs activate STAT signaling in cancer and TME cells. Supporting similar roles in tumors, increased STAT phosphorylation was also observed in tumors of breast cancer patients with high expression of LRRC, in proteomics data from TCGA. Thus, by regulating IL-6, LRRC may function as a driver of pathological angiogenesis and inflammation in breast cancer. Indeed, we observed that LRRC promotes endothelial sprouting angiogenesis and an inflammatory transcriptional program in CAFs and TME cells. Suggesting tumor-promoting roles of LRRC, high levels of LRRC correlate with worsened survival of breast cancer patients in TCGA datasets. To determine the influence of LRRC + CAFs on the surrounding TME, we are utilizing spatial proteomic analysis of breast cancer patient tissues. Together, our findings position LRRC as a central regulator of inflammatory signaling in breast cancer. By functioning upstream of IL-6 and driving activation of STAT, LRRC emerges as a key molecular nexus linking hypoxia to the iCAF phenotype and its tumor-promoting functions. The discovery of microenvironmental factors that fuel breast cancer inflammation is a sought-after milestone in the field since it may lead to the development of novel therapeutic interventions aimed at disrupting stromal-driven inflammation and tumor progression.
利益披露 Disclosure
F. G. Kugeratski, None..
L. Neilson, None..
A. Kacperczyk-Perdyan, None..
J. R. Hernandez-Fernaud, None..
S. Lilla, None..
J. Mieczkowski, None..
S. Zanivan, None.