Tumorigenic Metaplasia in Colorectal Cancer Delineated Through Applied Systems Theory

Abstract

Complex systems contain several hierarchical levels of abstracted information and function, which attenuate the effectiveness of traditional analytical methods. The application of systems theory and machine learning for the understanding of biological systems has become a new paradigm of data-driven science, especially in the context of human disease and cancer. Colorectal cancers (CRCs) arise from precursor polyps whose cellular origins, molecular heterogeneity, and immunogenic potential may reveal diagnostic and therapeutic insights when analyzed in high resolution. Tangentially, we have also shown that methods developed for the dissection of CRCs are generalizable to macro-scale complex systems such as healthcare organizations (HCOs). These systems-oriented frameworks enable the context-aware mining of human-computer interactions (HCIs). Ultimately, 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, which is driven partly by antigen presentation differences associated with tumor cell differentiation states. Resulting microsatellite instable CRCs evolve distinct non-metaplastic regions where tumor cells acquire stem properties and cytotoxic immune cells are depleted. These models are supported by multiple genetically engineered mouse models of colonic tumorigenesis involving differential cells-of-origin. Our multi-omic atlas provides paradigm-shifting insights into malignant progression of colorectal polyps and their microenvironments, serving as a framework for precision surveillance and prevention of CRC.