Epithelial Plasticity and an Immune Suppressive Microenvironment Underpin Tumour Budding in Colorectal Cancer

作者：Phimmada Hatthakarnkul, Natalie C. Fisher, Leonor Schubert Santana, Holly Leslie, Assya Legrini, Aula Ammar, Amna Matly, Kathryn A.F. Pennel, Ian Powley, Courtney Bull, Peter Alexander, Janos Sztanko, Jean A. Quinn, Jennifer Hay, Hannah Morgan, Claire Kennedy‐Dietrich, Yoana Doncheva, Gerard Lynch, Noori Maka, Hester C. van Wyk, Andrew D. Campbell, Xiao Fu, Donald McMillan, Owen J. Sansom, Philip D. Dunne, Nigel B. Jamieson, Campbell S.D. Roxburgh, Chanitra Thuwajit, Joanne Edwards · 发表于：bioRxiv (Cold Spring Harbor Laboratory) · 年份：2025 · DOI：10.1101/2025.03.05.641608 · 被引用次数：1 · 研究领域：Cancer Immunotherapy and Biomarkers、Colorectal Cancer Treatments and Studies、Inflammatory mediators and NSAID effects

Abstract Background Tumour budding (TB), defined as a small cluster of up to four cells at the invasive front of the tumour, is a well-established independent and robust prognostic biomarker in colorectal cancer (CRC). This is strongly associated with adverse clinicopathological features and poor survival outcomes. Despite its clinical relevance, the precise underlying mechanism responsible for TB phenomenon remains unclear. Methods Multi-omic approaches from bulk, regional GeoMx and Spatial Molecular Imager (SMI) RNA were used to identify the underlying mechanism of TB and its possible correlation with tumour microenvironment (TME) in CRC tissue. The results were validated using immunohistochemistry (IHC) and multiplex immunofluorescence (mIF) staining. Results Patients with high TB experience worse outcomes and associate with adverse clinical factors across two independent CRC cohorts. Bulk and regional RNA expression analyses reveal that tumours with high TB are significantly enriched for TNF-α and TGF-β signatures in both cohorts. Single cell CosMx SMI analysis confirmed TB cells exhibit higher expression of these signatures than adjacent invasive edge tumour cells. Elevated cyclinD1 expression was also observed within TB, and high cyclinD1 levels tend to experience poorer CRC prognosis. Furthermore, regional bulk RNA expression within the non-tumour (PanCK-) invasive edge areas demonstrated that tumours exhibiting high TB revealed the significantly differential expressio...