PanIN and CAF transitions in pancreatic carcinogenesis revealed with spatial data integration.

Visium Xenium imaging mass cytometry machine learning multi-omics pancreatic adenocarcinoma pancreatic intraepithelial neoplasia spatial transcriptomics transfer learning

Journal

Cell systems
ISSN: 2405-4720
Titre abrégé: Cell Syst
Pays: United States
ID NLM: 101656080

Informations de publication

Date de publication:
02 Aug 2024
Historique:
received: 07 07 2023
revised: 06 02 2024
accepted: 08 07 2024
medline: 9 8 2024
pubmed: 9 8 2024
entrez: 8 8 2024
Statut: aheadofprint

Résumé

This study introduces a new imaging, spatial transcriptomics (ST), and single-cell RNA-sequencing integration pipeline to characterize neoplastic cell state transitions during tumorigenesis. We applied a semi-supervised analysis pipeline to examine premalignant pancreatic intraepithelial neoplasias (PanINs) that can develop into pancreatic ductal adenocarcinoma (PDAC). Their strict diagnosis on formalin-fixed and paraffin-embedded (FFPE) samples limited the single-cell characterization of human PanINs within their microenvironment. We leverage whole transcriptome FFPE ST to enable the study of a rare cohort of matched low-grade (LG) and high-grade (HG) PanIN lesions to track progression and map cellular phenotypes relative to single-cell PDAC datasets. We demonstrate that cancer-associated fibroblasts (CAFs), including antigen-presenting CAFs, are located close to PanINs. We further observed a transition from CAF-related inflammatory signaling to cellular proliferation during PanIN progression. We validate these findings with single-cell high-dimensional imaging proteomics and transcriptomics technologies. Altogether, our semi-supervised learning framework for spatial multi-omics has broad applicability across cancer types to decipher the spatiotemporal dynamics of carcinogenesis.

Identifiants

DOI: 10.1016/j.cels.2024.07.001 PMID: 39116880
pubmed: 39116880
pii: S2405-4712(24)00183-2
doi: 10.1016/j.cels.2024.07.001
pii:
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Informations de copyright

Copyright © 2024 Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests E.M.J. reports other support from Abmeta; personal fees from Genocea; personal fees from Achilles; personal fees from DragonFly; personal fees from Candel Therapeutics; other support from the Parker Institute; grants and other support from Lustgarten; personal fees from Carta; grants and other support from Genentech; grants and other support from AstraZeneca; personal fees from NextCure; and grants and other support from Break Through Cancer outside of the submitted work. E.J.F. is on the Scientific Advisory Board of Viosera Therapeutics/Resistance Bio and is a consultant to Mestag Therapeutics. W.J.H. reports patent royalties from Rodeo/Amgen and speaking/travel honoraria from Exelixis and Standard BioTools.

Auteurs

Alexander T F Bell (ATF)

Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Jacob T Mitchell (JT)

Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Bloomberg Kimmel Immunology Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA.

Ashley L Kiemen (AL)

Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, MD, USA; Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD, USA.

Melissa Lyman (M)

Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Kohei Fujikura (K)

Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD, USA.

Jae W Lee (JW)

Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Bloomberg Kimmel Immunology Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD, USA.

Erin Coyne (E)

Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Bloomberg Kimmel Immunology Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Sarah M Shin (SM)

Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Bloomberg Kimmel Immunology Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Sushma Nagaraj (S)

Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Atul Deshpande (A)

Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Bloomberg Kimmel Immunology Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Pei-Hsun Wu (PH)

Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, MD, USA.

Dimitrios N Sidiropoulos (DN)

Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Bloomberg Kimmel Immunology Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Rossin Erbe (R)

Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Bloomberg Kimmel Immunology Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA.

Jacob Stern (J)

10x Genomics, Pleasanton, CA, USA.

Rena Chan (R)

10x Genomics, Pleasanton, CA, USA.

Stephen Williams (S)

10x Genomics, Pleasanton, CA, USA.

James M Chell (JM)

10x Genomics, Pleasanton, CA, USA.

Lauren Ciotti (L)

Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Jacquelyn W Zimmerman (JW)

Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Bloomberg Kimmel Immunology Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA; The Skip Viragh Center for Clinical and Translational Research, Baltimore, MD, USA.

Denis Wirtz (D)

Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, MD, USA; Department of Materials Science and Engineering, The Johns Hopkins University, Baltimore, MD, USA; Johns Hopkins Physical Sciences - Oncology Center, The Johns Hopkins University, Baltimore, MD, USA.

Won Jin Ho (WJ)

Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Bloomberg Kimmel Immunology Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA; The Skip Viragh Center for Clinical and Translational Research, Baltimore, MD, USA.

Neeha Zaidi (N)

Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Bloomberg Kimmel Immunology Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA; The Skip Viragh Center for Clinical and Translational Research, Baltimore, MD, USA.

Elizabeth Thompson (E)

Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD, USA; The Skip Viragh Center for Clinical and Translational Research, Baltimore, MD, USA.

Elizabeth M Jaffee (EM)

Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Bloomberg Kimmel Immunology Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA; The Skip Viragh Center for Clinical and Translational Research, Baltimore, MD, USA.

Laura D Wood (LD)

Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD, USA; The Skip Viragh Center for Clinical and Translational Research, Baltimore, MD, USA.

Elana J Fertig (EJ)

Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Bloomberg Kimmel Immunology Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Applied Mathematics and Statistics, Whiting School of Engineering, Johns Hopkins University, Baltimore, MD, USA; The Skip Viragh Center for Clinical and Translational Research, Baltimore, MD, USA. Electronic address: ejfertig@jhmi.edu.

Luciane T Kagohara (LT)

Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Bloomberg Kimmel Immunology Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA; The Skip Viragh Center for Clinical and Translational Research, Baltimore, MD, USA. Electronic address: ltsukam1@jhmi.edu.

Classifications MeSH