Differential pre-malignant programs and microenvironment chart distinct paths to malignancy in human colorectal polyps.
Differential pre-malignant programs and microenvironment chart distinct paths to malignancy in human colorectal polyps.
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DOI：
10.1016/j.cell.2021.11.031
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发表时间：
2021-12-22
期刊：
影响因子：
64.5
通讯作者：
Lau KS
中科院分区：
文献类型：
--
作者：
Chen B;Scurrah CR;McKinley ET;Simmons AJ;Ramirez-Solano MA;Zhu X;Markham NO;Heiser CN;Vega PN;Rolong A;Kim H;Sheng Q;Drewes JL;Zhou Y;Southard-Smith AN;Xu Y;Ro J;Jones AL;Revetta F;Berry LD;Niitsu H;Islam M;Pelka K;Hofree M;Chen JH;Sarkizova S;Ng K;Giannakis M;Boland GM;Aguirre AJ;Anderson AC;Rozenblatt-Rosen O;Regev A;Hacohen N;Kawasaki K;Sato T;Goettel JA;Grady WM;Zheng W;Washington MK;Cai Q;Sears CL;Goldenring JR;Franklin JL;Su T;Huh WJ;Vandekar S;Roland JT;Liu Q;Coffey RJ;Shrubsole MJ;Lau KS
结直肠癌（CRC）起源于前体息肉，其细胞起源、分子异质性和免疫原性潜力在高分辨率分析时可能揭示诊断和治疗见解。我们提出了一个单细胞转录和成像图谱的两个最常见的人类结直肠息肉，传统腺瘤和锯齿状息肉，以及由此产生的CRC对应。对来自62名参与者的128个数据集的综合分析表明，腺瘤是由WNT驱动的干细胞扩增引起的，而锯齿状息肉则是由胃化生的分化细胞引起的。化生相关损伤与超突变前的细胞毒性免疫微环境相关，部分由与肿瘤细胞分化状态相关的抗原呈递差异驱动。微卫星不稳定的CRC含有不同的非化生区域，其中肿瘤细胞获得干细胞特性并且细胞毒性免疫细胞被耗尽。我们的多组学图谱提供了对结直肠息肉及其微环境恶性进展的见解，可作为精确监测和预防CRC的框架。人类结直肠息肉的单细胞分辨率图谱绘制出癌前到癌症转化的不同路径，伴随着不同的免疫微环境特征。
Colorectal cancers (CRCs) arise from precursor polyps whose cellular origins, molecular heterogeneity, and immunogenic potential may reveal diagnostic and therapeutic insights when analyzed at high resolution. We present a single-cell transcriptomic and imaging atlas of the two most common human colorectal polyps, conventional adenomas and serrated polyps, and their resulting CRC counterparts. Integrative analysis of 128 datasets from 62 participants reveals adenomas arise from WNT-driven expansion of stem cells, while serrated polyps derive from differentiated cells through gastric metaplasia. Metaplasia-associated damage is coupled to a cytotoxic immune microenvironment preceding hypermutation, driven partly by antigen-presentation differences associated with tumor cell-differentiation status. Microsatellite unstable CRCs contain distinct non-metaplastic regions where tumor cells acquire stem cell properties and cytotoxic immune cells are depleted. Our multi-omic atlas provides insights into malignant progression of colorectal polyps and their microenvironment, serving as a framework for precision surveillance and prevention of CRC. A single-cell resolution atlas of human colorectal polyps maps out distinct paths for pre-cancer to cancer transformation, accompanied by differential immune microenvironment features.
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