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Dissecting FAP+ mesenchymal cell diversity and regulation uncovers an interferonresponse cancer-associated fibroblast subtype
Umeå University, Faculty of Medicine, Department of Radiation Sciences.
Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.ORCID iD: 0000-0002-5847-2778
(English)Manuscript (preprint) (Other academic)
National Category
Cancer and Oncology
Identifiers
URN: urn:nbn:se:umu:diva-215328OAI: oai:DiVA.org:umu-215328DiVA, id: diva2:1805678
Available from: 2023-10-18 Created: 2023-10-18 Last updated: 2023-10-18
In thesis
1. The identification and functional evaluation of novel cancer-associated fibroblast subtypes and matrisome proteins in pancreatic cancer
Open this publication in new window or tab >>The identification and functional evaluation of novel cancer-associated fibroblast subtypes and matrisome proteins in pancreatic cancer
2023 (English)Doctoral thesis, comprehensive summary (Other academic)
Alternative title[sv]
Identifiering och funktionell utvärdering av nya cancer-associerade fibroblast-subtyper och matrisomeproteiner i pankreascancer
Abstract [en]

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy characterized by an extensive desmoplastic stroma. The stroma is the site of intricate communication between malignant cells and their surrounding environment. This tissue microenvironment (TME) is populated by a heterogenous mixture of cell types and extracellular matrix proteins. Distinct stromal elements confer tumour-restraining or tumour-promoting influences on tumorigenesis. Characterizing stromal composition therefore represents an opportunity to identify candidates for therapeutic intervention to facilitate improved clinical outcomes. In this thesis we identify galectin-4 as an extracellular matrix protein which is upregulated in PDAC. We find that galectin-4 exerts a pro-tumorigenic influence in PDAC through promoting immune suppression, highlighting its potential as a novel therapeutic target. We subsequently provide a comprehensive characterization of mesenchymal cell diversity in PDAC including cancer-associated fibroblasts (CAFs) which represent one of the dominant stromal cellular components. We identify inflammatory CAF (iCAF) and myofibroblastic CAF (myCAF) subtypes in addition to defining a novel interferon-response CAF (ifCAF) subtype. In addition, we demonstrate that pancreatic stellate cells (PSCs) are capable of forming iCAFs, myCAFs and ifCAFs in response to tumour-derived signals using an organoid-based co-culture model and define biological pathways regulating CAF subtype formation. We then perform a high-throughput drug-screen using this co-culture model to identify compounds which can suppress tumour growth indirectly through modifying CAFs. One such compound is GNF-5 which we show can suppress cancer cell proliferation indirectly through manipulating CAF phenotype. Taken together, this thesis augments our understanding of the composition of the PDAC stroma and identifies potential therapeutic targets as well as developing an approach to discover drugs which yield a therapeutic benefit through targeting the PDAC stroma.   

Place, publisher, year, edition, pages
Umeå: Umeå University, 2023. p. 122
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 2259
Keywords
Cancer-associated fibroblast (CAF), Single-cell RNA sequencing (scRNAseq), Pancreatic ductal adenocarcinoma (PDAC), Tumor microenvironment (TME), Extracellular matrix (ECM), Organoid-based co-culture model, Drug-screen
National Category
Cancer and Oncology
Research subject
Oncology
Identifiers
urn:nbn:se:umu:diva-215330 (URN)9789180701747 (ISBN)9789180701754 (ISBN)
Public defence
2023-11-17, Betula, 6M, Norrlands universitetssjukhus, Umeå, 13:00 (English)
Opponent
Supervisors
Available from: 2023-10-26 Created: 2023-10-18 Last updated: 2023-10-19Bibliographically approved

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Cumming, JoshuaPatthey, CedricÖhlund, Daniel

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CiteExportLink to record
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Citation style
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