PO.CL01.12 · 临床研究

CDH1突变携带者中弥漫型胃癌从癌前病变到浸润性病变演进的空间三维与多组学图谱

Spatial 3D and multi-omics mapping of diffuse gastric cancer evolution from preinvasive to invasive lesions in CDH1 mutation carriers

编号 1201 展板 2 时间 4/19 02:00–05:00 区域 Section 47 主讲 Yunhe Liu, PhD

分会场 Spatial Proteomics and Transcriptomics 1

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作者与单位 Authors & Affiliations

Yunhe Liu¹, Idania Carolina Lubo Julio², Wei Lu², Alejandra G. Serrano², Jean R. Clemenceau³, Amber Famiglietti⁴, Karen Colbert⁵, Yibo Dai¹, Yang Liu¹, Jun Wang¹, Jeremy L. Davis⁶, Mingyao Li⁷, Paul F. Mansfield⁸, Tae Hyun Hwang³, Luisa M. Solis-Soto⁹, Linghua Wang¹

¹Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX,²Department of Translational and Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX,³Department of Surgery, Vanderbilt University Medical Center, Nashville, TN,⁴National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD,⁵Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX,⁶BioChemistry&Molecular Biology, University of Maryland School of Medicine, Baltimore, MD,⁷University of Pennsylvania, Philadelphia, PA,⁸Vice President, Acute Care Services, UT MD Anderson Cancer Ctr., Houston, TX,⁹Department of Translational Molecular Pathology, the university of MD Anderson cancer center, Houston, TX

摘要 Abstract

中文摘要

背景：遗传性弥漫型胃癌（DGC）缺乏明确的前驱病变序列。胚系CDH1功能丧失突变赋予高终生风险，无症状携带者的预防性胃切除术常发现大量隐匿的黏膜内印戒细胞（SRC）灶，这些病灶可多年保持惰性。从这些惰性SRC灶进展至浸润性DGC的生物学机制在很大程度上仍不明确。方法：我们对26例患者的原发性DGC进行分析，取样涵盖从SRC灶到浸润性病变及显著浸润前沿的完整组织学连续谱。全切片由病理学家注释肿瘤亚型及关键微环境特征。连续切片采用互补的空间多组学平台检测：GeoMx DSP、Visium、Xenium Prime 5K并后续行Codex（IO60），以及CosMx（WTX）。部分标本还使用Singular G4X进行高通量空间多组学测序（转录组/蛋白/TCR/BCR），并采用Singular G4X和全息断层成像（HT-X1）进行三维建模。跨平台数据集共配准至统一坐标；细胞分割、表型注释及邻域/生态位映射量化了从癌前到浸润性病变各区域的转录组动态及肿瘤微环境相互作用。Singular G4X与无标记全息断层成像的整合提供了三维背景。结果：空间转录组分析揭示了SRC至浸润连续谱上与浸润相关的转录程序。界定了与进展离散阶段相关的元程序（MPs）。整合组织学的分析突显了细胞周期、EMT及应激代谢通路随浸润深度的变化，轨迹/分化分析支持一条连续的浸润轴。拷贝数推断提示两条演化轨迹：线性和分支。单细胞分辨率空间多组学进一步细化了肿瘤细胞状态特征及其空间邻域，揭示早期病变以淋巴细胞为主的微环境状态，而随浸润加深呈现基质/髓系重塑，多重蛋白质组学（IO60）予以佐证。跨切片配准结合无标记三维全息断层成像生成了体积重建，映射出沿浸润轴的连贯克隆区段及一致的TME重塑。结论：我们呈现了DGC进展的空间多组学图谱。该工作以高空间和分子分辨率描绘了亚型和区域特异性基因程序、克隆结构及TME重塑，并以三维方式建模疾病进展。我们的发现确定了进展的候选生物标志物、风险分层以及CDH1突变携带者SRC肿瘤发生潜在治疗性拦截的可能。

查看英文原文 English abstract

Background: Hereditary diffuse-type gastric cancer (DGC) lacks a defined precursor sequence. Germline CDH1 loss-of-function mutations confer a high lifetime risk, and prophylactic gastrectomies in asymptomatic carriers frequently reveal numerous occult intramucosal signet-ring cell (SRC) foci that can remain indolent for years. The biological mechanisms underlying the progression from these indolent SRC foci to invasive DGC remain largely unknown. Methods: We profiled primary DGCs from 26 patients, sampling the full histologic continuum from SRC foci to invasive lesions and overtly invasive fronts. Whole-slide sections were pathologist-annotated for tumor subtype and key microenvironmental features. Serial sections were assayed with complementary spatial multi-omics platforms: GeoMx DSP, Visium, Xenium Prime 5K with post hoc Codex (IO60), and CosMx (WTX). Selected specimens also underwent high-plex spatial multi-omics sequencing (transcriptome/protein/TCR/BCR) using Singular G4X, as well as 3D modeling with both Singular G4X and holotomography (HT-X1). Cross-platform datasets were co-registered to common coordinates; cell segmentation, phenotype annotation, and neighborhood/niche mapping quantified transcriptomic dynamics and tumor-microenvironment interactions across regions spanning preinvasive to invasive lesions. Integration of Singular G4X and Label-free holotomography provided 3D context. Results: Spatial transcriptomic profiling revealed invasion-associated transcriptional programs along the SRC-to-invasive continuum. The meta-programs (MPs) associated with discrete stages of progression were defined. Histology-integrated analyses highlighted invasion-depth-dependent shifts in cell-cycle, EMT, and stress-metabolism pathways, and trajectory/differentiation analyses supported a continuous invasion axis. Copy-number inference indicated two evolution trajectories, linear and branched. Single-cell-resolution spatial multi-omics refined tumor cell-state signatures and their spatial neighborhoods, revealing lymphocyte-dominant microenvironmental states at early lesions and stromal/myeloid remodeling with deeper invasion, corroborated by multiplex proteomics (IO60). Cross-section registration with label-free 3D holotomography generated volumetric reconstructions mapping coherent clonal sectors and concordant TME remodeling along the invasion axis. Conclusions: We present a spatial multi-omic atlas of DGC progression. The work delineates subtype- and region-specific gene programs, clonal architectures, and TME remodeling at high spatial and molecular resolution, modeling disease progression in 3D. Our findings identify candidate biomarkers of progression, risk stratification, and potential therapeutic interception of SRC tumorigenesis in CDH1 mutation carriers.

利益披露 Disclosure

Y. Liu, None.. I. C. Lubo Julio, None.. W. Lu, None.. A. G. Serrano, None.. J. R. Clemenceau, None.. A. Famiglietti, None.. K. Colbert, None.. Y. Dai, None.. Y. Liu, None.. J. Wang, None.. J. L. Davis, None.. T. Hwang, None.. L. Wang, None.

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