PO.MCB09.06 · 分子与细胞生物学

CMS4结直肠癌CAFs中通过SREBP2驱动的胆固醇合成进行代谢重编程

Metabolic reprogramming through SREBP2-driven cholesterol synthesis in CAFs of CMS4 colorectal cancer

编号 4709 展板 7 时间 4/21 09:00–12:00 区域 Section 22 主讲 Iguru Omori, MBBS;MD

分会场 Metabolic Alterations in Colorectal and Gastrointestinal Cancers

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作者与单位 Authors & Affiliations

Iguru Omori¹, hiroaki kasashima¹, Yukina Kusunoki², Nobuhiro Naito¹, Zizhou Wang¹, Yuki Seki¹, Kenji Kuroda¹, Yuichiro Miki¹, Mami Yoshii¹, Tatsuro Tamura¹, Masatsune Shibutani¹, Takahiro Toyokawa¹, Masakazu Yashiro³, Yu Muta⁴, Yuki Nakanishi⁴, Kiyoshi Maeda¹

¹Department of Gastroenterological Surgery, Osaka Metropolitan University Graduate School of Med., Osaka, Japan,²Pathophysiology, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan,³Molecular Oncology and Therapeutics, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan,⁴Gastroenterology and Hepatology, Kyoto University, Kyoto, Japan

摘要 Abstract

中文摘要

结直肠癌已根据基因表达谱分层为共识分子亚型（CMS）。其中，间质亚型（CMS4）约占23%的病例，与其他亚型相比预后特别差。人们日益认识到，CMS4结直肠癌的高恶性度是由肿瘤基质（主要由CAFs构成）的激活及其在肿瘤微环境（TME）内与癌细胞的相互作用所驱动的。然而，其机制仍不明确。胆固醇对癌症至关重要，特别是通过其在膜完整性和细胞内信号传导中的作用。胆固醇稳态失调已被认为参与癌症进展。近期研究表明，SREBP2（胆固醇生物合成的关键转录因子）的激活促进了以促纤维增生为特征的侵袭性锯齿状结直肠肿瘤的发展。然而，癌症相关成纤维细胞（CAFs）的代谢状态，特别是关于胆固醇代谢方面，仍不清楚。我们分析了来自10例结直肠癌样本的批量RNA测序数据。进行了基因集富集分析（GSEA），以比较来自CMS4肿瘤的CAFs与来自其他CMS亚型的CAFs。随后，我们建立了源自CMS4和其他亚型肿瘤的CAF细胞系，并考察了CAF胆固醇代谢对肿瘤进展的影响。我们发现CMS4-CAFs表现出与胆固醇稳态相关基因集的显著富集。特别是，SREBP2及其下游基因的表达水平在CMS4-CAFs中显著上调。此外，我们的体外结果显示，抑制胆固醇生物合成或敲低SREBF2可降低CMS4-CAFs的增殖能力并抑制肿瘤迁移。这些发现凸显了CMS4结直肠癌中CAFs的一个潜在代谢特征，该特征可能有助于肿瘤的侵袭性。

查看英文原文 English abstract

Colorectal cancer has been stratified based on gene expression profiles into consensus molecular subtypes (CMS). Among these, the mesenchymal subtype (CMS4), which accounts for approximately 23% of cases, is associated with a particularly poor prognosis compared with the other subtypes. It has been increasingly recognized that the high malignancy of CMS4 colorectal cancer is driven by activation of the tumor stroma, predominantly composed of CAFs, and by its interactions with cancer cells within the tumor microenvironment (TME). However, the mechanisms remain to be unclear. Cholesterol is essential for cancer, particularly through its roles in membrane integrity and intracellular signaling. Dysregulation of cholesterol homeostasis has been implicated in cancer progression. Recent studies have shown that activation of SREBP2, a key transcription factor for cholesterol biosynthesis, contributes to the development of aggressive serrated colorectal tumors characterized by desmoplasia. However, the metabolic state of cancer-associated fibroblasts (CAFs), particularly regarding cholesterol metabolism, remains unclear. We analyzed bulk RNA sequencing data from 10 colorectal cancer samples. Gene set enrichment analysis (GSEA) was performed to compare CAFs from CMS4 tumors with those from other CMS subtypes. Subsequently, we established CAF lines derived from CMS4 and the other subtype tumors and examined the impact of CAF cholesterol metabolism on tumor progression. We revealed that CMS4-CAFs exhibited significant enrichment of gene sets related to cholesterol homeostasis. In particular expression levels of SREBP2 and its downstream genes were markedly upregulated in CMS4-CAFs. Furthermore our in vitro results showed that inhibition of cholesterol biosynthesis or SREBF2 knocking down reduced the proliferative capacity of CMS4-CAFs and suppressed tumor migration. These findings highlight a potential metabolic feature of CAFs in CMS4 colorectal cancer that may contribute to tumor aggressiveness.

利益披露 Disclosure

I. Omori, None. H. kasashima, Japan Agency of Medical Research and Development ). Y. Kusunoki, None.. N. Naito, None.. Z. Wang, None.. Y. Seki, None.. K. Kuroda, None.. Y. Miki, None.. M. Yoshii, None.. T. Tamura, None.. M. Shibutani, None.. T. Toyokawa, None.. M. Yashiro, None.. Y. Muta, None.. Y. Nakanishi, None.. K. Maeda, None.

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