Unraveling Host Glycobiology-Microbiome Interactions to Inform Precision Approaches in Colorectal Cancer

GlyCoNet-CRC investigates how host glycosylation patterns shape the carcinogenic microbiome within the colorectal cancer (CRC) tumor microenvironment, with a particular focus on Fusobacterium nucleatum and its recently identified polymicrobial consortia. The project addresses the following key research questions: (1) Which microbial consortia colonize CRC tumors? (2) How do microbial networks differ across tumors with different host “glycogene”expression and glycan profiles? (3) Which microbial adhesins mediate glycan-dependent colonization, invasion and persistence within the tumor microenvironment? (4) How do tumor-associated glycan profiles influence responses to conventional chemoradiotherapy in microsatellite-stable (MSS) CRC and to immunotherapy in microsatellite-instable (MSI) CRC. (5) Can co-culture models of clinically relevant bacterial consortia, established in transwell systems with commercially available cell lines and patient-derived primary cells or organoids, recapitulate clinical observations and serve as mechanistic platforms to study host–microbe interactions? (6) Can glyco-microbial biomarkers be identified for predicting therapeutic response and clinical outcome? (7) Do sex- and gender-specific factors influence microbiome composition, glycan profiles, or the functional effects of specific microbial consortia? The innovative core of the project lies in leveraging a large clinical biobank and integrating glycomics, microbiome profiling, and transcriptomic analyses to elucidate how tumor-specific glycan alterations drive microbial community assembly, adaptation, and pathogenicity – and/or vice versa. By combining patient-derived specimens, engineered cellular and organoid models, and multi-omics approaches, GlyCoNet-CRC establishes a novel precision medicine framework for CRC research. The project is expected to advance the development of predictive diagnostic tools, glycan-targeted therapeutic strategies, in vitro models for studying host–microbiome interactions, and microbiome-based risk stratification approaches, thereby redefining current concepts of CRC pathogenesis and treatment. Anchored by an interdisciplinary consortium of microbiologists, glycobiologists, surgeons, oncologists, and computational scientists, GlyCoNet-CRC will generate comprehensive open-access multi-omics datasets, glycoengineered model systems, and reproducible bioinformatic pipelines. These resources will be disseminated through repositories such as GEO, ENA, and GitHub, as well as through material transfer agreements (MTAs), thereby enabling future translational studies and supporting the development of glycan-modulating preventive, diagnostic, and therapeutic strategies in CRC.