Depicting the cellular complexity of pancreatic adenocarcinoma by Imaging Mass Cytometry: focus on cancer-associated fibroblasts.

Autor:	Erreni M; Unit of Multiscale and Nanostructural Imaging, IRCCS Humanitas Research Hospital, Milan, Italy.; Department of Biomedical Sciences, Humanitas University, Milan, Italy., Fumagalli MR; Unit of Multiscale and Nanostructural Imaging, IRCCS Humanitas Research Hospital, Milan, Italy., D'Anna R; Unit of Multiscale and Nanostructural Imaging, IRCCS Humanitas Research Hospital, Milan, Italy., Sollai M; Pathology Unit, IRCCS Humanitas Research Hospital, Milan, Italy., Bozzarelli S; Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Milan, Italy., Nappo G; Department of Biomedical Sciences, Humanitas University, Milan, Italy.; Pancreatic Surgery Unit, IRCCS Humanitas Research Hospital, Milan, Italy., Zanini D; Unit of Multiscale and Nanostructural Imaging, IRCCS Humanitas Research Hospital, Milan, Italy., Parente R; Unit of Multiscale and Nanostructural Imaging, IRCCS Humanitas Research Hospital, Milan, Italy., Garlanda C; Department of Biomedical Sciences, Humanitas University, Milan, Italy.; IRCCS Humanitas Research Hospital, Milan, Italy., Rimassa L; Department of Biomedical Sciences, Humanitas University, Milan, Italy.; Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Milan, Italy., Terracciano LM; Department of Biomedical Sciences, Humanitas University, Milan, Italy.; Pathology Unit, IRCCS Humanitas Research Hospital, Milan, Italy., Biswas SK; Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore., Zerbi A; Department of Biomedical Sciences, Humanitas University, Milan, Italy.; Pancreatic Surgery Unit, IRCCS Humanitas Research Hospital, Milan, Italy., Mantovani A; Department of Biomedical Sciences, Humanitas University, Milan, Italy.; IRCCS Humanitas Research Hospital, Milan, Italy.; William Harvey Research Institute, Queen Mary University of London, London, United Kingdom., Doni A; Unit of Multiscale and Nanostructural Imaging, IRCCS Humanitas Research Hospital, Milan, Italy.
Jazyk:	angličtina
Zdroj:	Frontiers in immunology [Front Immunol] 2024 Nov 07; Vol. 15, pp. 1472433. Date of Electronic Publication: 2024 Nov 07 (Print Publication: 2024).
DOI:	10.3389/fimmu.2024.1472433
Abstrakt:	Introduction: Pancreatic ductal adenocarcinoma (PDAC) represents the complexity of interaction between cancer and cells of the tumor microenvironment (TME). Immune cells affect tumor cell behavior, thus driving cancer progression. Cancer-associated fibroblasts (CAFs) are responsible of the desmoplastic and fibrotic reaction by regulating deposition and remodeling of extracellular matrix (ECM). As tumor-promoting cells abundant in PDAC ECM, CAFs represent promising targets for novel anticancer interventions. However, relevant clinical trials are hampered by the lack of specific markers and elusive differences among CAF subtypes. Indeed, while single-cell transcriptomic analyses have provided important information on the cellular constituents of PDACs and related molecular pathways, studies based on the identification of protein markers in tissues aimed at identifying CAF subtypes and new molecular targets result incomplete. Methods: Herein, we applied multiplexed Imaging Mass Cytometry (IMC) at single-cell resolution on 8 human PDAC tissues to depict the PDAC composing cells, and profiling immune cells, endothelial cells (ECs), as well as endocrine cells and tumor cells. Results: We focused on CAFs by characterizing up to 19 clusters distinguished by phenotype, spatiality, and interaction with immune and tumor cells. We report evidence that specific subtypes of CAFs (CAFs 10 and 11) predominantly are enriched at the tumor-stroma interface and closely associated with tumor cells. CAFs expressing different combinations of FAP, podoplanin and cadherin-11, were associated with a higher level of CA19-9. Moreover, we identified specific subsets of FAP + and podoplanin + /cadherin-11 + CAFs enriched in patients with negative prognosis. Discussion: The present study provides new general insights into the complexity of the PDAC microenvironment by defining phenotypic heterogeneities and spatial distributions of CAFs, thus suggesting different functions of their subtypes in the PDAC microenvironment. Competing Interests: LR reports grant/research funding to institution from Agios, AstraZeneca, BeiGene, Eisai, Exelixis, Fibrogen, Incyte, IPSEN, Lilly, MSD, Nerviano Medical Sciences, Roche, Servier, Taiho Oncology, TransThera Sciences, and Zymeworks; consulting fees from AbbVie, AstraZeneca, Basilea, Bayer, Bristol Myers Squibb, Elevar Therapeutics, Exelixis, Genenta, Hengrui, Incyte, IPSEN, IQVIA, Jazz Pharmaceuticals, MSD, Nerviano Medical Sciences, Roche, Servier, Taiho Oncology, and Zymeworks; lecture fees from AstraZeneca, Bayer, Bristol Myers Squibb, Guerbet, Incyte, IPSEN, Roche, and Servier; and travel expenses from AstraZeneca. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision. The reviewer MM declared a shared affiliation, with no collaboration, with the authors to the handling editor at the time of the review. (Copyright © 2024 Erreni, Fumagalli, D’Anna, Sollai, Bozzarelli, Nappo, Zanini, Parente, Garlanda, Rimassa, Terracciano, Biswas, Zerbi, Mantovani and Doni.)
Databáze:	MEDLINE
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