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

Alexander T F Bell; Jacob T Mitchell; Ashley L Kiemen; Melissa Lyman; Kohei Fujikura; Jae W Lee; Erin Coyne; Sarah M Shin; Sushma Nagaraj; Atul Deshpande; Pei-Hsun Wu; Dimitrios N Sidiropoulos; Rossin Erbe; Jacob Stern; Rena Chan; Stephen Williams; James M Chell; Lauren Ciotti; Jacquelyn W Zimmerman; Denis Wirtz; Won Jin Ho; Neeha Zaidi; Elizabeth Thompson; Elizabeth M Jaffee; Laura D Wood; Elana J Fertig; Luciane T Kagohara

doi:10.1016/j.cels.2024.07.001

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

Cell Syst. 2024 Aug 21;15(8):753-769.e5. doi: 10.1016/j.cels.2024.07.001. Epub 2024 Aug 7.

Authors

Alexander T F Bell¹, Jacob T Mitchell², Ashley L Kiemen³, Melissa Lyman¹, Kohei Fujikura⁴, Jae W Lee⁵, Erin Coyne⁶, Sarah M Shin⁶, Sushma Nagaraj¹, Atul Deshpande⁶, Pei-Hsun Wu⁷, Dimitrios N Sidiropoulos⁸, Rossin Erbe², Jacob Stern⁹, Rena Chan⁹, Stephen Williams⁹, James M Chell⁹, Lauren Ciotti¹, Jacquelyn W Zimmerman¹⁰, Denis Wirtz¹¹, Won Jin Ho¹⁰, Neeha Zaidi¹⁰, Elizabeth Thompson¹², Elizabeth M Jaffee¹⁰, Laura D Wood¹², Elana J Fertig¹³, Luciane T Kagohara¹⁴

Affiliations

¹ 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.
² 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.
³ Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, MD, USA; Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD, USA.
⁴ Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD, USA.
⁵ 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.
⁶ 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.
⁷ Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, MD, USA.
⁸ 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.
⁹ 10x Genomics, Pleasanton, CA, USA.
¹⁰ 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.
¹¹ 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.
¹² 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.
¹³ 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.
¹⁴ 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.

PMID: 39116880
PMCID: PMC11409191 (available on 2025-08-21)
DOI: 10.1016/j.cels.2024.07.001

Abstract

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.

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

MeSH terms

Cancer-Associated Fibroblasts* / metabolism
Carcinogenesis* / genetics
Carcinoma in Situ / genetics
Carcinoma in Situ / pathology
Carcinoma, Pancreatic Ductal* / genetics
Gene Expression Regulation, Neoplastic / genetics
Humans
Pancreatic Neoplasms* / genetics
Single-Cell Analysis / methods
Transcriptome / genetics
Tumor Microenvironment / genetics

Abstract

MeSH terms

Grants and funding