cover image: Pacpaint: a histology-based deep learning model uncovers the extensive intratumor molecular heterogeneity of pancreatic adenocarcinoma

20.500.12592/1bvst0d

Pacpaint: a histology-based deep learning model uncovers the extensive intratumor molecular heterogeneity of pancreatic adenocarcinoma

1 Dec 2023

Two tumor (Classical/Basal) and stroma (Inactive/active) subtypes of Pancreatic adenocarcinoma (PDAC) with prognostic and theragnostic implications have been described. These molecular subtypes were defined by RNAseq, a costly technique sensitive to sample quality and cellularity, not used in routine practice. To allow rapid PDAC molecular subtyping and study PDAC heterogeneity, we develop PACpAInt, a multi-step deep learning model. PACpAInt is trained on a multicentric cohort ( n = 202) and validated on 4 independent cohorts including biopsies (surgical cohorts n = 148; 97; 126 / biopsy cohort n = 25), all with transcriptomic data ( n = 598) to predict tumor tissue, tumor cells from stroma, and their transcriptomic molecular subtypes, either at the whole slide or tile level (112 µm squares). PACpAInt correctly predicts tumor subtypes at the whole slide level on surgical and biopsies specimens and independently predicts survival. PACpAInt highlights the presence of a minor aggressive Basal contingent that negatively impacts survival in 39% of RNA-defined classical cases. Tile-level analysis ( > 6 millions) redefines PDAC microheterogeneity showing codependencies in the distribution of tumor and stroma subtypes, and demonstrates that, in addition to the Classical and Basal tumors, there are Hybrid tumors that combine the latter subtypes, and Intermediate tumors that may represent a transition state during PDAC evolution.

Authors

Charlie Saillard, Flore Delecourt, Benoit Schmauch, Olivier Moindrot, Magali Svrcek, Armelle Bardier-Dupas, Jean Francois Emile, Mira Ayadi, Vinciane Rebours, Louis de Mestier, Pascal Hammel, Cindy Neuzillet, Jean Baptiste Bachet, Juan Iovanna, Nelson Dusetti, Yuna Blum, Magali Richard, Yasmina Kermezli, Valerie Paradis, Mikhail Zaslavskiy, Pierre Courtiol, Aurelie Kamoun, Remy Nicolle, Jerome Cros

Bibliographic Reference
Charlie Saillard, Flore Delecourt, Benoit Schmauch, Olivier Moindrot, Magali Svrcek, et al.. Pacpaint: a histology-based deep learning model uncovers the extensive intratumor molecular heterogeneity of pancreatic adenocarcinoma. Nature Communications, 2023, 14 (1), pp.3459. ⟨10.1038/s41467-023-39026-y⟩. ⟨hal-04164254⟩
DOI
https://doi.org/10.1038/s41467-023-39026-y
Funding
This work was granted access to the HPC resources of IDRIS under the allocation AD011012519 made by GENCI.
HAL Collection
['Université de Rennes 1', 'HAL Grenoble Alpes', 'IMAG', 'CNRS - Centre national de la recherche scientifique', 'Aix Marseille Université', 'Institut polytechnique de Grenoble', 'AP-HP', 'SFR Biosit - Biologie et Santé CNRS UMS 3480', 'UNICANCER', 'Institut Curie', 'Institut Paoli-Calmettes', 'Institut Génétique et Développement de Rennes', 'Université de Versailles Saint-Quentin-en-Yvelines', "UFR SVE Sciences de la vie et de l'environnement", 'Publications labos UR1 dans HAL-Rennes 1', 'Université Paris sciences et lettres', 'UR1 - publications SDV', 'Université Paris-Saclay', 'TEST Université de Rennes CSS', 'Université de Rennes', 'Sorbonne Université', 'Sorbonne Université 01/01/2018', 'Centre de Recherche en Cancérologie de Marseille', 'Faculté de Santé de Sorbonne Université', 'Médecine - Sorbonne Université', 'Université de Lyon', 'Université Paris Cité', 'Université de Paris - Faculté de Santé', 'Institut Curie - PSL', 'UVSQ-UPSACLAY', 'Université Grenoble Alpes [2020-*]', 'Sorbonne Université - Texte Intégral', 'Pôle Rennes 1 - Biologie-Santé', 'Alliance Sorbonne Université', 'Biologie et génétique du cancer']
HAL Identifier
4221280
Institution
['Owkin France', 'Institut National de la Santé et de la Recherche Médicale', 'Université Paris Cité', 'Hôpital Beaujon [AP-HP]', 'CHU Saint-Antoine [AP-HP]', 'CHU Pitié-Salpêtrière [AP-HP]', 'Hôpital Ambroise Paré [AP-HP]', 'Université de Versailles Saint-Quentin-en-Yvelines', 'IntegraGen', 'Hôpital Paul Brousse', 'Institut Curie [Paris]', 'Aix Marseille Université', 'Institut Paoli-Calmettes', 'Université de Rennes', 'Structure Fédérative de Recherche en Biologie et Santé de Rennes', "VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement", 'Institut polytechnique de Grenoble - Grenoble Institute of Technology']
Laboratory
["Centre de recherche sur l'Inflammation", 'INTEGRAGEN', 'Centre de Recherche en Cancérologie de Marseille', 'Institut de Génétique et Développement de Rennes', 'Translational Innovation in Medicine and Complexity', 'Recherche Translationnelle et Innovation en Médecine et Complexité - UMR 5525']
Published in
France

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