Kavli Affiliate: Denis Wirtz
| Authors: Alexander T.F. Bell, Jacob T. Mitchell, Ashley L. Kiemen, Kohei Fujikura, Helen Fedor, Bonnie Gambichler, Atul Deshpande, Pei-Hsun Wu, Dimitrios N Sidiropoulos, Rossin Erbe, Jacob Stern, Rena Chan, Stephen Williams, James M. Chell, Jacquelyn W Zimmerman, Denis Wirtz, Elizabeth M. Jaffee, Laura D. Wood, Elana J. Fertig and Luciane T. Kagohara
| Summary:
Spatial transcriptomics (ST) is a powerful approach for cancers molecular and cellular characterization. Pancreatic intraepithelial neoplasia (PanIN) is a pancreatic ductal adenocarcinoma (PDAC) premalignancy diagnosed from formalin-fixed and paraffin-embedded (FFPE) specimens limiting single-cell based investigations. We developed a new FFPE ST analysis protocol for PanINs complemented with novel transfer learning approaches. The first transfer learning approach, to assign cell types to ST spots and integrate the transcriptional signatures, shows that PanINs are surrounded by PDAC cancer associated fibroblasts (CAFs) subtypes, including the rare antigen-presenting CAFs. Furthermore, most PanINs are of the classical PDAC subtype while one sample expresses cancer stem cell markers. A second transfer learning approach, to integrate ST PanIN data with PDAC scRNA-seq data, identifies a shift between inflammatory and proliferative signaling as PanINs progress to PDAC. Our data support a model of inflammatory signaling and PanIN-CAF interactions promoting premalignancy progression and PDAC immunosuppressive characteristics. Significance We developed a novel FFPE spatial transcriptomics analysis pipeline to profile the heterogeneous CAF and malignant epithelial cells in PanINs, premalignant lesions that can progress to invasive PDAC. This study identifies for the first time similar CAF populations residing in PanINs and associated molecular changes that together may be early mediators of premalignant transformation to PDAC. Competing Interest Statement 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. No disclosures were reported by the other authors.