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Differential pre-malignant programs and microenvironment chart distinct paths to malignancy in human colorectal polyps


Chen BBob , Scurrah CRCherie' R , McKinley ETEliot T , Simmons AJAlan J , Ramirez-Solano MAMarisol A , Zhu XXiangzhu , Markham NONicholas O , Heiser CNCody N , Vega PNPaige N , Rolong AAndrea , Kim HHyeyon , Sheng QQuanhu , Drewes JLJulia L , Zhou YYuan , Southard-Smith ANAustin N , Xu YYanwen , Ro JJames , Jones ALAngela L , Revetta FFrank , Berry LDLynne D , Niitsu HHiroaki , Islam MMirazul , Pelka KKarin , Hofree MMatan , Chen JHJonathan H , Sarkizova SSiranush , Ng KKimmie , Giannakis MMarios , Boland GMGenevieve M , Aguirre AJAndrew J , Anderson ACAna C , Rozenblatt-Rosen OOrit , Regev AAviv , Hacohen NNir , Kawasaki KKenta , Sato TToshiro , Goettel JAJeremy A , Grady WMWilliam M , Zheng WWei , Washington MKM Kay , Cai QQiuyin , Sears CLCynthia L , Goldenring JRJames R , Franklin JLJeffrey L , Su TTimothy , Huh WJWon Jae , Vandekar SSimon , Roland JTJoseph T , Liu QQi , Coffey RJRobert J , Shrubsole MJMartha J , Lau KSKen S . Cell. 2021 12 14; 184(26). 6262-6280.e26


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.