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The identification and functional evaluation of novel cancer-associated fibroblast subtypes and matrisome proteins in pancreatic cancer
Umeå University, Faculty of Medicine, Department of Radiation Sciences.
2023 (English)Doctoral thesis, comprehensive summary (Other academic)Alternative title
Identifiering och funktionell utvärdering av nya cancer-associerade fibroblast-subtyper och matrisomeproteiner i pankreascancer (Swedish)
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 [en]
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: urn:nbn:se:umu:diva-215330ISBN: 9789180701747 (print)ISBN: 9789180701754 (electronic)OAI: oai:DiVA.org:umu-215330DiVA, id: diva2:1805713
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
List of papers
1. Extracellular galectin 4 drives immune evasion and promotes T-cell apoptosis in pancreatic cancer
Open this publication in new window or tab >>Extracellular galectin 4 drives immune evasion and promotes T-cell apoptosis in pancreatic cancer
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2023 (English)In: Cancer immunology research, ISSN 2326-6066, Vol. 11, no 1, p. 72-92Article in journal (Refereed) Published
Abstract [en]

Pancreatic ductal adenocarcinoma (PDAC) is characterized by rich deposits of extracellular matrix (ECM), affecting the pathophysiology of the disease. Here, we identified galectin 4 (gal 4) as a cancer cell produced protein deposited into the ECM of PDAC tumors and detected high circulating levels of gal 4 in PDAC patients. In orthotopic transplantation experiments we observed increased infiltration of T-cells and prolonged survival in immunocompetent mice transplanted with cancer cells with reduced expression of gal 4. Increased survival was not observed in immunodeficient RAG1-/- mice, demonstrating that the effect was mediated by the adaptive immune system. Furthermore, by performing single-cell RNA-sequencing we found that the myeloid compartment and cancer-associated fibroblast (CAF) subtypes were altered in the transplanted tumors. Reduced gal 4 expression was associated with higher proportion of myofibroblastic CAFs and reduced numbers of inflammatory CAFs. We also found higher proportions of M1 macrophages, T-cells and antigen presenting dendritic cells in tumors with reduced gal 4 expression. Using a co-culture system, we observed that extracellular gal 4 induced apoptosis in T-cells by binding N-glycosylation residues on CD3 epsilon/delta. Hence, we show that gal 4 is involved in immune evasion and identify gal 4 as a promising drug target for overcoming immunosuppression in PDAC. 

Place, publisher, year, edition, pages
American Association for Cancer Research, 2023
Keywords
Galectin 4, pancreatic cancer, immunosuppression, extracellular matrix, drug target
National Category
Cancer and Oncology
Research subject
Immunology; Medicine; Oncology
Identifiers
urn:nbn:se:umu:diva-201042 (URN)10.1158/2326-6066.CIR-21-1088 (DOI)36478037 (PubMedID)2-s2.0-85145492684 (Scopus ID)
Funder
The Swedish Foundation for International Cooperation in Research and Higher Education (STINT), PT2015-6432Swedish Cancer Society, AMP17-877, LP18-2202, LP20-2257, LP 21-2298Swedish Research Council, 2017-01531The Kempe Foundations, JCK-1301, SMK-1765Swedish Society of Medicine, SLS-890521, SLS-786661, SLS-691681, SLS-591551Västerbotten County Council, RV-930167, VLL-643451, VLL-832001Sjöberg FoundationKnut and Alice Wallenberg FoundationMarianne and Marcus Wallenberg Foundation, MMW 2020.0189Swedish Cancer Society, CAN 2017/332, CAN 2017/827, 20 1339 PjFSwedish Cancer Society, AMP-18-919Knut and Alice Wallenberg Foundation
Note

Originally included in thesis in manuscript form. 

Available from: 2022-11-16 Created: 2022-11-16 Last updated: 2023-10-18Bibliographically approved
2. Dissecting FAP+ mesenchymal cell diversity and regulation uncovers an interferonresponse cancer-associated fibroblast subtype
Open this publication in new window or tab >>Dissecting FAP+ mesenchymal cell diversity and regulation uncovers an interferonresponse cancer-associated fibroblast subtype
(English)Manuscript (preprint) (Other academic)
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-215328 (URN)
Available from: 2023-10-18 Created: 2023-10-18 Last updated: 2023-10-18
3. Potentiating the tumor-restraining properties of the stroma in pancreatic cancer with small molecules
Open this publication in new window or tab >>Potentiating the tumor-restraining properties of the stroma in pancreatic cancer with small molecules
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(English)Manuscript (preprint) (Other academic)
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-215329 (URN)
Available from: 2023-10-18 Created: 2023-10-18 Last updated: 2023-10-18

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Cumming, Joshua

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