PO.CL01.12 · 临床研究

利用空间转录组学剖析结肠癌结构识别出具有临床相关性的间质生态型

Profiling colon cancer architecture with spatial transcriptomics identifies clinically relevant stromal ecotypes

编号 1216 展板 17 时间 4/19 02:00–05:00 区域 Section 47 主讲 Sophie Mouillet-Richard, PhD

分会场 Spatial Proteomics and Transcriptomics 1

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作者与单位 Authors & Affiliations

Antoine Cazelles¹, Camilla Pilati¹, Delphine Le Corre¹, Gadea Cabrejas¹, Marine Sroussi¹, Claire Mulot¹, Claire Gallois¹, Gilles Manceau¹, Mehdi Karoui¹, Isaias Hernández-Verdin¹, Antoine Bougoüin¹, Wolf-Herman Fridman¹, Aurélien de Reyniès¹, Côme Lepage², Thierry Andre³, Jean-François Emile⁴, Théo Z. Hirsch¹, Julien Taieb¹, Pierre Laurent-Puig¹, Sophie Mouillet-Richard¹

¹Centre de Recherche des Cordeliers, Paris, France,²University of Burgundy and Franche Comté, Dijon, France,³Hôpital Saint-Antoine, Paris, France,⁴Ambroise-Paré Hospital, Boulogne, France

摘要 Abstract

中文摘要

尽管在理解结肠癌肿瘤内异质性方面取得了进展，但构成结肠肿瘤的细胞类型和状态的空间组织仍有待充分阐明。我们构建了一个包含48例III期结肠癌的大型空间转录组图谱，并识别出反复出现的、具有生物学相关性的空间生态系统，包括肿瘤和间质生态型。对复发相关谱的分析揭示了一组基因的间质特异性上调，其中包括再生/复兴干细胞（REC/RSC）标志物ANXA1。疾病复发伴随着REC/RSC和YAP激活特征的间质特异性富集，以及ANXA1水平与胶原表达基因水平之间关联的增加。对间质区室的剖析揭示了隐藏的异质性以及复发患者中ANXA1和相关标志物的亚簇特异性富集。利用Visium HD在单细胞分辨率下进一步分析，能够在以丰富的产生胶原的癌相关成纤维细胞（CAF）为标志的环境中定位表达ANXA1的肿瘤细胞。最后，我们通过进行单变量和多变量分析将这些发现转化为bulk转录组学，并在三个独立队列（包含>3,500例II期和III期结肠癌患者）中证明了源自空间生态型和间质亚簇的基因特征的预后价值。通过绘制局限性结肠癌中的细胞生态系统，这项工作为阐明疾病复发机制和指导治疗策略奠定了基础。空间来源的预后特征在bulk转录组数据中的验证为其潜在整合到临床实践以改善患者分层铺平了道路。

查看英文原文 English abstract

Despite progress in the understanding of intra-tumor heterogeneity in colon cancer, the spatial organization of the cell types and states that compose colon tumors remains to be fully delineated. We constructed a large spatial transcriptomic atlas of 48 stage III colon cancers and identified recurrent, biologically relevant spatial ecosystems, including tumor and stromal ecotypes. Analysis of recurrence-associated profiles revealed a stromal-specific upregulation of a set of genes that includes the regenerative/revival-stem cell (REC/RSC) marker ANXA1 . Disease recurrence was accompanied by stromal-specific enrichment of REC/RSC and YAP activation signatures, together with increased associations between levels of ANXA1 and those of collagen-expressing genes. Dissection of the stromal compartment uncovered hidden heterogeneity and sub-cluster-specific enrichment in ANXA1 and related markers in patients with relapse. Further profiling at single cell resolution with Visium HD allowed spotting ANXA1 -expressing tumor cells within an environment marked by abundant collagen-producing cancer-associated fibroblasts (CAFs). Finally, we translated these findings to bulk transcriptomics by performing univariate and multivariate analyses and demonstrated the prognostic value of gene signatures derived from the spatial ecotypes and stromal sub-clusters across three independent cohorts comprising >3,500 stage II and stage III colon cancer patients. By mapping cellular ecosystems in localized colon cancer, this work lays the foundation to elucidate mechanisms of disease recurrence and inform therapeutic strategies. The validation of the spatially-derived prognostic signatures in bulk transcriptomic data paves the way for their potential integration into clinical practice to improve patient stratification.

利益披露 Disclosure

A. Cazelles, None.. C. Pilati, None.. D. Le Corre, None.. G. Cabrejas, None.. M. Sroussi, None.. C. Mulot, None.. C. Gallois, None.. G. Manceau, None.. M. Karoui, None.. I. Hernández-Verdin, None.. A. Bougoüin, None.. W. Fridman, None.. A. de Reyniès, None. C. Lepage, Novartis Other, Advisory. AAA Other, Advisory. AMGEN Other, Speaker fees. Bayer Other, Speaker fees. T. Andre, Aptitude health Other, Consulting. Abbvie Other, Consulting. Biocartis Other, Consulting. BMS Travel, Other, Consulting and lecture fees. Gritstone Bio Other, Consulting. GSK Other, Consulting and lecture fees. MSD Oncology Travel, Other, Consulting and lecture fees. Medicenna Other, Consulting. Nimbus Other, Consulting. Nordic Bioscience Other, Consulting. Sanofi Other, Consulting and lecture fees. Servier Other, Consulting and lecture fees. Pfizer Other, Consulting. Takeda/Lundbeck Other, Consulting. Merck Serono Other, Lecture fees. Roche/Genentech Other, Lecture fees. Seagen Other, Lecture fees. Inspirna Other, DMC member role. J. Emile, None.. T. Z. Hirsch, None. J. Taieb, AMGEN Other, Consultancy and speaker fees. Astellas Other, Consultancy and speaker fees. BMS Other, Consultancy and speaker fees. Merck Travel, Other, Consultancy and speaker fees. MSD Other, Consultancy and speaker fees. Novartis ), Other, Consultancy and speaker fees. Pfizer Other, Consultancy. Pierre Fabre ), Travel, Other, Consultancy and speaker fees. Rottapharm Other, Consultancy. Sanofi Other, Consultancy. Servier ), Travel, Other, Consultancy and speaker fees. Takeda Travel, Other, Consultancy and speaker fees. Natera ), Other, Speaker fees. P. Laurent-Puig, AMGEN Other, Advisory or speaker fees. Servier Other, Advisory or speaker fees. Pierre Fabre Other, Advisory or speaker fees. Biocartis Advisory or speaker fees. Methys DX Stock. S. Mouillet-Richard, None.

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