TY - JOUR T1 - Multiplexed 3D atlas of state transitions and immune interactions in colorectal cancer JF - bioRxiv DO - 10.1101/2021.03.31.437984 SP - 2021.03.31.437984 AU - Jia-Ren Lin AU - Shu Wang AU - Shannon Coy AU - Madison Tyler AU - Clarence Yapp AU - Yu-An Chen AU - Cody N. Heiser AU - Ken S. Lau AU - Sandro Santagata AU - Peter K. Sorger Y1 - 2021/01/01 UR - http://biorxiv.org/content/early/2021/04/02/2021.03.31.437984.abstract N2 - Advanced solid cancers are complex assemblies of tumor, immune, and stromal cells that invade adjacent tissue and spread to distant sites. Here we use highly multiplexed tissue imaging, spatial statistics, and machine learning to identify cell types and states underlying morphological features of known diagnostic and prognostic significance in colorectal cancer. We find that a thorough spatial analysis requires imaging the entire tumor region, not small fields of view (e.g. those found in tissue microarrays). When this condition is met, the data reveal frequent transitions between histological archetypes (tumor grades and morphologies) correlated with molecular gradients. At the tumor invasive margin, where tumor, normal, and immune cells compete, localized features in 2D such as tumor buds and mucin pools are seen in 3D to be large connected structures having continuously varying molecular properties. Immunosuppressive cell-cell interactions also exhibit graded variation in type and frequency. Thus, whereas scRNA-Seq emphasizes discrete changes in tumor state, whole-specimen imaging reveals the presence of large- and small-scale spatial gradients analogous to those in developing tissues.Competing Interest StatementPKS is a member of the SAB or BOD member of Applied Biomath, RareCyte Inc., and Glencoe Software, which distributes a commercial version of the OMERO database; PKS is also a member of the NanoString SAB. In the last five years the Sorger lab has received research funding from Novartis and Merck. Sorger declares that none of these relationships have influenced the content of this manuscript. SS is a consultant for RareCyte Inc. ER -