1. Tumour spheres with inverted polarity drive the formation of peritoneal metastases in patients with hypermethylated colorectal carcinomas.
- Author
-
Zajac O, Raingeaud J, Libanje F, Lefebvre C, Sabino D, Martins I, Roy P, Benatar C, Canet-Jourdan C, Azorin P, Polrot M, Gonin P, Benbarche S, Souquere S, Pierron G, Nowak D, Bigot L, Ducreux M, Malka D, Lobry C, Scoazec JY, Eveno C, Pocard M, Perfettini JL, Elias D, Dartigues P, Goéré D, and Jaulin F
- Subjects
- Animals, Biomarkers, Tumor metabolism, Caco-2 Cells, Colorectal Neoplasms metabolism, Epithelial Cells metabolism, Genetic Predisposition to Disease, Humans, Mice, Inbred NOD, Mice, SCID, Neoplasm Invasiveness, Peritoneal Neoplasms metabolism, Phenotype, Prospective Studies, Signal Transduction, Time Factors, Transforming Growth Factor beta metabolism, Tumor Cells, Cultured, Tumor Microenvironment, Biomarkers, Tumor genetics, Cell Movement, Cell Polarity, Colorectal Neoplasms genetics, Colorectal Neoplasms pathology, DNA Methylation, Epithelial Cells pathology, Peritoneal Neoplasms genetics, Peritoneal Neoplasms secondary
- Abstract
Metastases account for 90% of cancer-related deaths; thus, it is vital to understand the biology of tumour dissemination. Here, we collected and monitored >50 patient specimens ex vivo to investigate the cell biology of colorectal cancer (CRC) metastatic spread to the peritoneum. This reveals an unpredicted mode of dissemination. Large clusters of cancer epithelial cells displaying a robust outward apical pole, which we termed tumour spheres with inverted polarity (TSIPs), were observed throughout the process of dissemination. TSIPs form and propagate through the collective apical budding of hypermethylated CRCs downstream of canonical and non-canonical transforming growth factor-β signalling. TSIPs maintain their apical-out topology and use actomyosin contractility to collectively invade three-dimensional extracellular matrices. TSIPs invade paired patient peritoneum explants, initiate metastases in mice xenograft models and correlate with adverse patient prognosis. Thus, despite their epithelial architecture and inverted topology TSIPs seem to drive the metastatic spread of hypermethylated CRCs.
- Published
- 2018
- Full Text
- View/download PDF