PO.TB10.02 · 肿瘤生物学

多组学整合揭示转移性结直肠癌中由巨噬细胞免疫抑制驱动的鞘氨醇-1-磷酸/神经酰胺变阻器失衡

Multiomics integration unveils a shifted balance in the sphingosine-1 phosphate/ceramide rheostat fueled by macrophage immunosuppression in metastatic colorectal cancer

编号 6126 展板 17 时间 4/21 02:00–05:00 区域 Section 28 主讲 Michelle Maurin, MS

分会场 Metastasis and Organ-Specific Microenvironmental Evolution

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作者与单位 Authors & Affiliations

Michelle M. Maurin¹, Siddabasave Gowda B. Gowda², Divyavani Gowda³, Heiman Wang¹, Michael Nebozhyn⁴, Ramani Soundararajan¹, Mckayla Carr¹, Punith M Sundaraswamy⁵, Ashley Alden¹, Carolina Martinez¹, Robert David Bennett¹, Allen Chudzinski¹, Andreas Karachristos¹, Timothy M. Nywening¹, Paul M. Cavallaro¹, Matthew Linley Anderson¹, Robert J. Coffey⁶, Michael Schell⁷, Jorge Marcet¹, Richard Jacobson¹, Andrey Loboda⁴, Ganesh V. Halade⁸, Mingli Yang¹, Lance Pflieger⁹, Warren Jackson Pledger¹⁰, Shu-Ping Hui³, Timothy J. Yeatman¹

¹Department of Surgery, University of South Florida, Tampa, FL,²Graduate School of Global Food Resources and Faculty of Health Sciences, Hokkaido University, Sapporo, Japan,³Faculty of Health Sciences, Hokkaido University, Sapporo, Japan,⁴Director, Informatics&Analysis, Merck & Co., Inc., Boston, MA,⁵Graduate School of Global Food Resources, Hokkaido University, Sapporo, Japan,⁶Vanderbilt University Medical Center, Nashville, TN,⁷Biostatistics and Bioinformatics Department, Moffitt Cancer Center, Tampa, FL,⁸Department of Internal Medicine, University of South Florida, Tampa, FL,⁹Buck Institute for Research on Aging, Center for Phenom Health., Novato, CA,¹⁰Tampa General Hospital and Department of Molecular Medicine, University of South Florida, Tampa, FL

摘要 Abstract

中文摘要

背景三十年前，基于神经酰胺的促凋亡作用与鞘氨醇-1-磷酸（S1P）的促存活作用，提出了 S1P/神经酰胺“鞘氨醇变阻器”模型，其中在癌症中，变阻器向由神经酰胺增强合成 S1P 的方向倾斜，使比值增加。然而，支持该假说的人肿瘤数据非常有限。目的利用定量多组学，在一大批（n = 629）人结直肠癌（CRC）中探索 S1P/神经酰胺代谢通路内脂质合成的平衡。设计对 525 例原发和 104 例转移性 CRC（mCRC）进行定量 LC-MS/MS 分析。完成了结合定量脂质组学与全转录组学、选定基因的定量 RT-PCR 及临床数据的整合多组学分析。结果我们证明 mCRC 与原发标本相比相对富集 S1P 和二氢鞘氨醇-1-磷酸（Sa1P），而长链神经酰胺（24:1）则相对减少。对一大批（n = 2200）CRC 患者数据集的基因表达分析和 CRC 的 qRT-PCR 显示，合成 S1P/Sa1P 的酶及其受体在 mCRC 中富集并与不良预后相关。scRNA-seq 分析显示它们的表达主要存在于髓系细胞中。最后，一个三基因 S1P 巨噬细胞相关特征与分期和患者生存相关。结论我们的发现界定了 S1P/神经酰胺合成中一种与不良预后和癌症进展相关的失衡，可归因于肿瘤微环境中的促炎性巨噬细胞，验证了 mCRC 中的鞘氨醇变阻器假说。

查看英文原文 English abstract

Background Thirty years ago, a S1P/ceramide “sphingosine rheostat” model was proposed based on ceramide's pro-apoptotic vs . sphingosine-1 phosphate (S1P) pro-survival role, where in cancer, the rheostat tilts towards enhanced synthesis of S1P from ceramides, increasing the ratio. Human tumor data supporting the hypothesis, however, are very limited. Objective To leverage quantitative multi-omics to explore the balance in the synthesis of lipids within the S1P/Ceramide metabolic pathway in a large set (n = 629) of human colorectal cancers (CRC). Design Quantitative LC-MS/MS analysis was performed on 525 primary and 104 metastatic CRC (mCRC). An integrative multi-omics analysis combining quantitative lipidomics with whole transcriptomics, quantitative RT-PCR of selected genes and clinical data was completed. Results We demonstrated that mCRC versus primary specimens are relatively enriched in S1P and sphinganine-1-P (Sa1P), whereas the long chain ceramides (24:1) are relatively decreased. Gene-expression analysis of a large (n = 2200) CRC patient dataset and qRT-PCR of CRC revealed that S1P/Sa1P-synthesizing enzymes and their receptors are enriched in mCRC and are linked to poor prognosis. scRNA-seq analysis showed that their expression prevailed in myeloid cells. Finally, a three-gene S1P macrophage-associated signature correlated with stage and patient survival. Conclusion Our findings define an imbalance in the synthesis of S1P/Ceramide linked to poor prognosis and cancer progression, and attributable to proinflammatory macrophages in the tumor microenvironment, validating the sphingosine rheostat hypothesis in mCRC.

利益披露 Disclosure

M. M. Maurin, None.. S. G. Gowda, None.. D. Gowda, None.. H. Wang, None.. M. Nebozhyn, None.. R. Soundararajan, None.. M. Carr, None.. P. M Sundaraswamy, None.. A. Alden, None.. C. Martinez, None.. R. D. Bennett, None.. A. Chudzinski, None.. A. Karachristos, None.. T. M. Nywening, None.. P. M. Cavallaro, None.. M. L. Anderson, None.. M. Schell, None.. J. Marcet, None.. R. Jacobson, None.. G. V. Halade, None.. M. Yang, None.. L. Pflieger, None.. W. J. Pledger, None.. S. Hui, None.. T. J. Yeatman, None.

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