INSERM-U981 Institut Gustave Roussy, Villejuif.
"Collective epithelial-based metastases in colorectal carcinoma patients"
As a critical step in cancer progression and a challenge to patient treatment, tumour cell dissemination has been the subject of intense investigation across a range of model systems, in vitro and in animals. These studies have led to the assumption that the fatal progression of carcinoma is associated with a loss of epithelial architecture and polarity1-3 as single tumour cells escape from the primary tumour to reach secondary sites4,5. However, these studies have been performed using experimental model systems and the mechanisms driving metastatic spread in cancer patients remain under-investigated. Here, we collected and monitored over 50 patient specimens ex vivo to investigate the cell biology of colorectal cancer (CRC) metastasis as it spreads to the peritoneum. This reveals a new mode of cancer dissemination. Large clusters of cancer epithelial cells displaying an inverted apico-basolateral polarity, which we term Tumour Spheres with Inverted Polarity (TSIPs), were observed throughout the process of tumour dissemination. We show that TSIPs form and propagate through the collective apical budding of hyper-methylated neoplastic tissues. Despite their inverted topology, TSIPs collectively invade extracellular matrices, paired patients¹ peritoneum explants and initiate metastases in mice xenograft models. Further, the presence of TSIPs in peritoneal effusions correlates with metastases burden and adverse patient prognosis. Thus, despite their having a robust epithelial architecture, TSIPs appear to drive the peritoneal dissemination of CRC, as well as other primary cancers, such as breast carcinoma. By applying cell biological methods to live primary cancer specimens, we provide an alternative conception of cancer dissemination that goes against the prevailing consensus and could not be anticipated from experimental model systems.