Patient-derived organoids identify an apico-basolateral polarity switch associated with survival in colorectal cancer

• DOI: 10.1242/jcs.259256
• Publication Date: 2022-06-15T08:57:59Z
• Authors: Charlotte Canet-J...; Diane-Laure Pagès; Clémence Nguyen-V...; Jérôme Cartry; Olivier Zajac; Christophe Desterke; Jean-Baptiste Lopez; Emie Gutierrez-Ma...; Nicolas Signolle; Julien Adam; Joel Raingeaud; Mélanie Polrot; Patrick Gonin; Jacques R. R. Mat...; Sylvie Souquere; Gerard Pierron; Maximiliano Gelli; Peggy Dartigues; Michel Ducreux; Valeria Barresi; Fanny Jaulin
• Keywords: 0301 basic medicine; 0303 health sciences; [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology; 3. Good health; Organoids; 03 medical and health sciences; [SDV.CAN] Life Sciences [q-bio]/Cancer; Apicobasolateral polarity; Colorectal cancer; Integrins; Organoids; TGFbeta; Transforming Growth Factor beta; [SDV.BC.BC] Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC]; Cell Adhesion; Humans; Colorectal Neoplasms; Signal Transduction

ABSTRACT The metastatic progression of cancer remains a major issue in patient treatment. However, the molecular and cellular mechanisms underlying this process remain unclear. Here, we use primary explants and organoids from patients harboring mucinous colorectal carcinoma (MUC CRC), a poor-prognosis histological form of digestive cancer, to study the architecture, invasive behavior and chemoresistance of tumor cell intermediates. We report that these tumors maintain a robust apico-basolateral polarity as they spread in the peritumoral stroma or organotypic collagen-I gels. We identified two distinct topologies – MUC CRCs either display a conventional ‘apical-in’ polarity or, more frequently, harbor an inverted ‘apical-out’ topology. Transcriptomic analyses combined with interference experiments on organoids showed that TGFβ and focal adhesion signaling pathways are the main drivers of polarity orientation. Finally, we show that the apical-out topology is associated with increased resistance to chemotherapeutic treatments in organoids and decreased patient survival in the clinic. Thus, studies on patient-derived organoids have the potential to bridge histological, cellular and molecular analyses to decrypt onco-morphogenic programs and stratify cancer patients. This article has an associated First Person interview with the first author of the paper.