PO.CL12.01 · 临床研究

通过对新鲜冷冻内镜活检标本进行全面磷酸化蛋白质组学实现结直肠癌的磷酸化蛋白质组分型与表征

Phosphoproteomic subtyping and characterization of colorectal cancer by comprehensive phosphoproteomics of fresh frozen endoscopic biopsy specimens

编号 3874 展板 7 时间 4/20 02:00–05:00 区域 Section 46 主讲 Jun Adachi, PhD

分会场 Molecular Classification and Tumor Biology in Cancer

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作者与单位 Authors & Affiliations

Jun Adachi¹, Hirokazu Shoji², Hidekazu Hirano², Yosui Nojima³, Satoshi Muraoka¹, Yutaka Saito², Ken Kato², Narikazu Boku⁴, Yukihide Kanemitsu²

¹National Institute of -Biomedical Innovation, Health, and Nutrition, Osaka, Japan,²National Cancer Center Hospital, Tokyo, Japan,³The University of Osaka, OIsaka, Japan,⁴University of Tokyo, Tokyo, Japan

摘要 Abstract

中文摘要

背景与目的：磷酸化是一种调控蛋白质活性、定位和相互作用的关键翻译后修饰。通过绘制磷酸化模式，磷酸化蛋白质组学可实时揭示癌细胞如何重编程其信号网络以促进生长、存活、转移和治疗耐药。传统的深度磷酸化蛋白质组学需要相对大量的临床样本，而我们开发了一种利用内镜活检样本的高灵敏度方法，可为磷酸化蛋白质组分析提供优良的质量。在本研究中，我们评估了结直肠癌（CRC）患者新鲜冷冻内镜活检样本中的磷酸化蛋白质组图谱。方法：从102例未经治疗的CRC患者获取内镜活检标本，并在采集后20秒内于液氮中速冻。使用基于串联质谱标签（TMT）的多重标记进行超深度蛋白质组和磷酸化蛋白质组分析。基因组分析采用基于靶向高多重PCR的下一代测序（NGS）panel进行。结果：使用204例未经治疗的结直肠癌标本和204例肿瘤旁正常组织（NAT）进行基于超灵敏质谱的蛋白质组学分析，平均定量了23985个磷酸化位点。共识聚类将结直肠癌清晰地划分为亚型1（增殖型，33%）、亚型2（EMT型，25%）、亚型3（代谢型，20%）和亚型4（异常RNA剪接型，21%）。从磷酸化蛋白质组数据中获得了激酶活性谱，并识别出在每种亚型中特异性激活或失活的激酶。虽然这些磷酸化蛋白质组亚型与共识分子亚型（CMS）之间的一致性较低，但肿瘤和NAT的偏侧性与不同的激酶组活性相关。结论：这项概念验证研究表明，磷酸化蛋白质组分析能够独立于CMS分类划分CRC亚型，并提供详细的激酶活性图谱。我们的开创性方法能够从小型内镜活检中实现稳健的临床磷酸化蛋白质组学，为监测治疗性激酶活性和推进精准肿瘤学提供了有前景的工具。

查看英文原文 English abstract

Background and Aims: Phosphorylation is a key post-translational modification that regulates protein activity, localization, and interactions. By mapping phosphorylation patterns, phosphoproteomics provides real-time insights into how cancer cells reprogram their signaling networks to promote growth, survival, metastasis, and therapy resistance. While conventional deep phosphoproteomics requires a relatively large amount of clinical samples, we have developed a highly sensitive method using endoscopic biopsy samples which can offer excellent quality for hosphoproteomic analysis. In this study we evaluated the phosphoproteomic landscape in fresh-frozen endoscopic biopsies from patients with colorectal cancer (CRC). Methods: Endoscopic biopsy specimens were obtained from 102 treatment-naïve CRC patients and snap-frozen in liquid nitrogen within 20 seconds of collection. Ultra-deep proteome and phosphoproteome analyses were performed using tandem mass tag (TMT)-based multiplexing. Genomic profiling was conducted with a targeted, high-multiplex PCR-based next-generation sequencing (NGS) panel. Results: Ultrasensitive mass spectrometry-based proteomics using 204 naïve colorectal cancer specimens and 204 normal tissue adjacent to the tumor (NAT) quantified an average of 23985 phosphorylation sites. Consensus clustering clearly divided colorectal cancer into subtype 1 (proliferative type, 33%), subtype 2 (EMT type, 25%), Subtype 3 (Metabolic type, 20%), and subtype 4 (Abnormal RNA splicing type, 21%). Kinase activity profiles were obtained from phosphoproteome data and kinases that are specifically activated or inactivated in each subtype were identified. While concordance between these phosphoproteomic subtypes and the consensus molecular subtypes (CMS) was low, sidedness was associated with different kinome activity of tumor and NAT. Conclusions: This proof-of-concept study demonstrates that phosphoproteomic analysis can delineate CRC subtypes independent of CMS classification and provide detailed kinase activity landscapes. Our pioneering approach enables robust clinical phosphoproteomics from small endoscopic biopsies, offering a promising tool for monitoring therapeutic kinase activities and advancing precision oncology.

利益披露 Disclosure

J. Adachi, ONO Pharma ). Boelinger Ingelheim ). Mitsubishi Tanabe Pharma ). Takeda ). Stemrim ). Kirin ). Proteobiologics Stock. H. Shoji, MSD ). Astellas ). AstraZeneca ). AbbVie ). Taiho Pharmaceutical ). Daiichi Sankyo ). Ono Pharma ). Elevation Oncology ). Chugai ). Metagen Therapeutics ). H. Hirano, Bristol-Myers Squibb ), Other, honoraria. Ono Pharmaceutical Other, honoraria. Novartis ), Other, honoraria. Daiichi-Sankyo ), Other, honoraria. Taiho Pharmaceutical Other, honoraria. PPD ). Nippon Boehringer Ingelheim ). ALX Oncology ). BeiGene ). Amgen ). Seagen ). Y. Nojima, None.. S. Muraoka, None.. Y. Saito, None. K. Kato, Bristol Myers Squibb ), Other, Consulting fees, honoraria. Merck Sharp & Dohme ), Other, Consulting fees. BeiGene ), Other, Consulting fees. Roche Other, Consulting fees. AstraZeneca ), Other, Consulting fees. Bayer ), Other, Consulting fees. Ono Pharmaceutical Other, honoraria. Taiho pharmaceutical Other, honoraria. Ono Pharmaceutical ). Chugai ). Shionogi ). N. Boku, Astellas Other, honoraria. Bristol Myers Squibb Other, honoraria. Taiho Other, honoraria. Y. Kanemitsu, None.

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