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

Author:

Canet-Jourdan Charlotte1ORCID,Pagès Diane-Laure1,Nguyen-Vigouroux Clémence1,Cartry Jérôme1,Zajac Olivier2,Desterke Christophe3ORCID,Lopez Jean-Baptiste1,Gutierrez-Mateyron Emie4ORCID,Signolle Nicolas5,Adam Julien5ORCID,Raingeaud Joel1,Polrot Mélanie6,Gonin Patrick6ORCID,Mathieu Jacques R. R.1,Souquere Sylvie7ORCID,Pierron Gerard7,Gelli Maximiliano8ORCID,Dartigues Peggy9,Ducreux Michel810ORCID,Barresi Valeria11ORCID,Jaulin Fanny1ORCID

Affiliation:

1. INSERM U-1279, Gustave Roussy 1 , Villejuif F-94805 , France

2. Institut Curie, PSL Research University, CNRS UMR 144 2 , F-75005 Paris , France

3. INSERM UMR-S-MD A9, Hôpital Paul Brousse 3 , Villejuif F-94805 , France

4. INSERM U-1030, Gustave Roussy 4 , Villejuif F-94805 , France

5. INSERM Unit U981, Experimental Pathology, Gustave Roussy 5 , 94805 Villejuif , France

6. Plateforme d'Evaluation Préclinique, AMMICA UMS 3655/ US 23, Gustave Roussy 6 , Villejuif F-94805 , France

7. UMR-9196, Gustave Roussy 7 , Villejuif F-94805 , France

8. Gustave Roussy 8 Department of Medical Oncology , , Villejuif F-94805 , France

9. Gustave Roussy 9 Pathology Department , , Villejuif F-94805 , France

10. Paris-Saclay University 10 , Saint-Aubin F-91190 , France

11. University of Verona 11 Department of Diagnostics and Public Health , , Verona 37129 , Italia

Abstract

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.

Funder

Institut National Du Cancer

Agence Nationale de la Recherche

Institut National de la Santé et de la Recherche Médicale

Ligue Contre le Cancer

Gustave Roussy Foundation

Paris-Saclay University

French Ministry of Superior Education

Fondation Pour la Recherche Médicale

Publisher

The Company of Biologists

Subject

Cell Biology

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