Roles of THBS2 fibroblasts in malignant transformation of colorectal polyp to cancer.

Colorectal cancer (CRC) typically originates from benign polyps within the colorectum. However, the mechanisms driving this transformation remain poorly understood. In this study, we employed a comprehensive multi-omics approach, incorporating multiplex immunostaining and adeno-associated virus (AAV)-mediated mouse models, to systematically dissect the key drivers of malignant transformation in CRC. Our investigations revealed a dynamic and stage-specific expression pattern of thrombospondin 2 (encoded by the gene THBS2), characterized by significantly downregulated expression during the polyp stage, followed by markedly upregulated expression in malignant CRC tissues compared to healthy colon tissue. Intriguingly, THBS2 expression was primarily localized within a distinct fibroblast subpopulation, with THBS2 fibroblasts exhibiting a tumor-tropic infiltration pattern. Through a series of analyses, we hypothesized that THBS2 fibroblasts may play a role in coordinating CRC progression via the THBS2-CD36 and THBS2-SDC1 pathways. Furthermore, depletion of THBS2 fibroblasts enhanced polyp formation but suppressed tumor formation in a thymidine kinase 1/ganciclovir/azoxymethane/dextran sulfate sodium mouse model. The comprehensive multi-omics atlas and complementary data presented here will advance our understanding of the mechanisms underlying CRC malignant transformation and may provide a potential therapeutic target. © 2026 The Pathological Society of Great Britain and Ireland.