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Mason, James E.
Publications (6 of 6) Show all publications
Mason, J. E. & Öhlund, D. (2023). Key aspects for conception and construction of co-culture models of tumor-stroma interactions. Frontiers in Bioengineering and Biotechnology, 11, Article ID 1150764.
Open this publication in new window or tab >>Key aspects for conception and construction of co-culture models of tumor-stroma interactions
2023 (English)In: Frontiers in Bioengineering and Biotechnology, E-ISSN 2296-4185, Vol. 11, article id 1150764Article, review/survey (Refereed) Published
Abstract [en]

The tumor microenvironment is crucial in the initiation and progression of cancers. The interplay between cancer cells and the surrounding stroma shapes the tumor biology and dictates the response to cancer therapies. Consequently, a better understanding of the interactions between cancer cells and different components of the tumor microenvironment will drive progress in developing novel, effective, treatment strategies. Co-cultures can be used to study various aspects of these interactions in detail. This includes studies of paracrine relationships between cancer cells and stromal cells such as fibroblasts, endothelial cells, and immune cells, as well as the influence of physical and mechanical interactions with the extracellular matrix of the tumor microenvironment. The development of novel co-culture models to study the tumor microenvironment has progressed rapidly over recent years. Many of these models have already been shown to be powerful tools for further understanding of the pathophysiological role of the stroma and provide mechanistic insights into tumor-stromal interactions. Here we give a structured overview of different co-culture models that have been established to study tumor-stromal interactions and what we have learnt from these models. We also introduce a set of guidelines for generating and reporting co-culture experiments to facilitate experimental robustness and reproducibility.

Place, publisher, year, edition, pages
Frontiers Media S.A., 2023
Keywords
cancer associated fibroblasts, cell culture models, co-culture, organoid, tumor-stroma interactions
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-208065 (URN)10.3389/fbioe.2023.1150764 (DOI)000975436300001 ()37091337 (PubMedID)2-s2.0-85153519815 (Scopus ID)
Funder
Cancerforskningsfonden i Norrland, LP20-2257Cancerforskningsfonden i Norrland, LP 21-2298Cancerforskningsfonden i Norrland, LP22-2332Swedish Research Council, 2017-01531Swedish Research Council, 2022-00855Swedish Society of Medicine, SLS-890521Region Västerbotten, RV-930167Region Västerbotten, RV-978812Knut and Alice Wallenberg FoundationMarianne and Marcus Wallenberg Foundation, MMW 2020.0189Swedish Cancer Society, 20 1339 PjF
Available from: 2023-05-29 Created: 2023-05-29 Last updated: 2023-05-29Bibliographically approved
Bhuma, N., Chand, K., Andréasson, M., Mason, J. E., Das, R. N., Patel, A. K., . . . Chorell, E. (2023). The effect of side chain variations on quinazoline-pyrimidine G-quadruplex DNA ligands. European Journal of Medicinal Chemistry, 248, Article ID 115103.
Open this publication in new window or tab >>The effect of side chain variations on quinazoline-pyrimidine G-quadruplex DNA ligands
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2023 (English)In: European Journal of Medicinal Chemistry, ISSN 0223-5234, E-ISSN 1768-3254, Vol. 248, article id 115103Article in journal (Refereed) Published
Abstract [en]

G-quadruplex (G4) DNA structures are involved in central biological processes such as DNA replication and transcription. These DNA structures are enriched in promotor regions of oncogenes and are thus promising as novel gene silencing therapeutic targets that can be used to regulate expression of oncoproteins and in particular those that has proven hard to drug with conventional strategies. G4 DNA structures in general have a well-defined and hydrophobic binding area that also is very flat and featureless and there are ample examples of G4 ligands but their further progression towards drug development is limited. In this study, we use synthetic organic chemistry to equip a drug-like and low molecular weight central fragment with different side chains and evaluate how this affect the compound's selectivity and ability to bind and stabilize G4 DNA. Furthermore, we study the binding interactions of the compounds and connect the experimental observations with the compound's structural conformations and electrostatic potentials to understand the basis for the observed improvements. Finally, we evaluate the top candidates' ability to selectively reduce cancer cell growth in a 3D co-culture model of pancreatic cancer which show that this is a powerful approach to generate highly active and selective low molecular weight G4 ligands with a promising therapeutic window.

Place, publisher, year, edition, pages
Elsevier, 2023
National Category
Medicinal Chemistry
Identifiers
urn:nbn:se:umu:diva-202112 (URN)10.1016/j.ejmech.2023.115103 (DOI)000922160800001 ()2-s2.0-85146280645 (Scopus ID)
Funder
The Kempe Foundations, SMK-1632Swedish Research Council, 2017–05235Swedish Research Council, 2017- 01531The Swedish Medical Association, SLS-890521Region Västerbotten, RV-930167Knut and Alice Wallenberg FoundationMarianne and Marcus Wallenberg Foundation, 2020.0189Swedish Cancer Society, 20 1339 PjFCancerforskningsfonden i Norrland, LP 21–2298Cancerforskningsfonden i Norrland, LP 22–2332
Note

Originally included in thesis in manuscript form.

Available from: 2023-01-02 Created: 2023-01-02 Last updated: 2023-09-05Bibliographically approved
Mason, J. E., Lundberg, E., Jonsson, P., Nyström, H., Franklin, O., Lundin, C., . . . Öhlund, D. (2022). A cross-sectional and longitudinal analysis of pre-diagnostic blood plasma biomarkers for early detection of pancreatic cancer. International Journal of Molecular Sciences, 23(21), Article ID 12969.
Open this publication in new window or tab >>A cross-sectional and longitudinal analysis of pre-diagnostic blood plasma biomarkers for early detection of pancreatic cancer
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2022 (English)In: International Journal of Molecular Sciences, ISSN 1661-6596, E-ISSN 1422-0067, Vol. 23, no 21, article id 12969Article in journal (Refereed) Published
Abstract [en]

Pancreatic ductal adenocarcinoma (PDAC) is a major cause of cancer death that typically presents at an advanced stage. No reliable markers for early detection presently exist. The prominent tumor stroma represents a source of circulating biomarkers for use together with cancer cell-derived biomarkers for earlier PDAC diagnosis. CA19-9 and CEA (cancer cell-derived biomarkers), together with endostatin and collagen IV (stroma-derived) were examined alone, or together, by multivariable modelling, using pre-diagnostic plasma samples (n = 259 samples) from the Northern Sweden Health and Disease Study biobank. Serial samples were available for a subgroup of future patients. Marker efficacy for future PDAC case prediction (n = 154 future cases) was examined by both cross-sectional (ROC analysis) and longitudinal analyses. CA19-9 performed well at, and within, six months to diagnosis and multivariable modelling was not superior to CA19-9 alone in cross-sectional analysis. Within six months to diagnosis, CA19-9 (AUC = 0.92) outperformed the multivariable model (AUC = 0.81) at a cross-sectional level. At diagnosis, CA19-9 (AUC = 0.995) and the model (AUC = 0.977) performed similarly. Longitudinal analysis revealed increases in CA19-9 up to two years to diagnosis which indicates a window of opportunity for early detection of PDAC.

Place, publisher, year, edition, pages
MDPI, 2022
Keywords
analysis, biomarkers, carcinoma, early detection of cancer, pancreatic ductal, tumor, tumor microenvironment
National Category
Cancer and Oncology
Research subject
Surgery
Identifiers
urn:nbn:se:umu:diva-201220 (URN)10.3390/ijms232112969 (DOI)000881359700001 ()36361759 (PubMedID)2-s2.0-85141870302 (Scopus ID)
Funder
Swedish Research Council, 2017-01531Swedish Research Council, 2016-02990Swedish Research Council, 2019-01690Swedish Research Council, 2017-00650The Kempe Foundations, JCK-1301Swedish Society of Medicine, SLS-890521Swedish Society of Medicine, SLS-786661Region Västerbotten, RV-930167Västerbotten County Council, VLL-643451Västerbotten County Council, VLL-832001Region Västerbotten, RV-583411Region Västerbotten, RV-549731Region Västerbotten, RV-841551Region Västerbotten, 930132Region Västerbotten, RV-930167Cancerforskningsfonden i Norrland, LP20-2257Cancerforskningsfonden i Norrland, LP18-2202Cancerforskningsfonden i Norrland, LP18-2192Cancerforskningsfonden i Norrland, LP21-2298Cancerforskningsfonden i Norrland, LP22-2332Sjöberg FoundationKnut and Alice Wallenberg Foundation, KAW 2015.0114Marianne and Marcus Wallenberg Foundation, MMW 2020.0189Swedish Cancer Society, CAN 2017/332Swedish Cancer Society, CAN 2017/827Swedish Cancer Society, CAN 2011/751Swedish Cancer Society, CAN 2016/643Swedish Cancer Society, 19 0273Swedish Cancer Society, 20 1339
Available from: 2022-12-15 Created: 2022-12-15 Last updated: 2023-06-08Bibliographically approved
Maneshi, P., Mason, J., Dongre, M. & Öhlund, D. (2021). Targeting Tumor-Stromal Interactions in Pancreatic Cancer: Impact of Collagens and Mechanical Traits. Frontiers in Cell and Developmental Biology, 9, Article ID 787485.
Open this publication in new window or tab >>Targeting Tumor-Stromal Interactions in Pancreatic Cancer: Impact of Collagens and Mechanical Traits
2021 (English)In: Frontiers in Cell and Developmental Biology, E-ISSN 2296-634X, Vol. 9, article id 787485Article, review/survey (Refereed) Published
Abstract [en]

Pancreatic ductal adenocarcinoma (PDAC) has one of the worst outcomes among cancers with a 5-years survival rate of below 10%. This is a result of late diagnosis and the lack of effective treatments. The tumor is characterized by a highly fibrotic stroma containing distinct cellular components, embedded within an extracellular matrix (ECM). This ECM-abundant tumor microenvironment (TME) in PDAC plays a pivotal role in tumor progression and resistance to treatment. Cancer-associated fibroblasts (CAFs), being a dominant cell type of the stroma, are in fact functionally heterogeneous populations of cells within the TME. Certain subtypes of CAFs are the main producer of the ECM components of the stroma, with the most abundant one being the collagen family of proteins. Collagens are large macromolecules that upon deposition into the ECM form supramolecular fibrillar structures which provide a mechanical framework to the TME. They not only bring structure to the tissue by being the main structural proteins but also contain binding domains that interact with surface receptors on the cancer cells. These interactions can induce various responses in the cancer cells and activate signaling pathways leading to epithelial-to-mesenchymal transition (EMT) and ultimately metastasis. In addition, collagens are one of the main contributors to building up mechanical forces in the tumor. These forces influence the signaling pathways that are involved in cell motility and tumor progression and affect tumor microstructure and tissue stiffness by exerting solid stress and interstitial fluid pressure on the cells. Taken together, the TME is subjected to various types of mechanical forces and interactions that affect tumor progression, metastasis, and drug response. In this review article, we aim to summarize and contextualize the recent knowledge of components of the PDAC stroma, especially the role of different collagens and mechanical traits on tumor progression. We furthermore discuss different experimental models available for studying tumor-stromal interactions and finally discuss potential therapeutic targets within the stroma.

Place, publisher, year, edition, pages
Frontiers Media S.A., 2021
Keywords
collagen, extracellular matrix, mechanical traits, pancreatic cancer, PDAC—pancreatic ductal adenocarcinoma, stroma
National Category
Cell and Molecular Biology Cancer and Oncology
Research subject
Oncology
Identifiers
urn:nbn:se:umu:diva-190614 (URN)10.3389/fcell.2021.787485 (DOI)34901028 (PubMedID)2-s2.0-85120962866 (Scopus ID)
Funder
EU, Horizon 2020, 861196Swedish Research Council, 2017-01531Region Västerbotten, RV-930167Region Västerbotten, VLL-832001Cancerforskningsfonden i Norrland, LP 21-2298Marianne and Marcus Wallenberg Foundation, MMW 2020.0189Swedish Cancer Society, CAN 2017/332Swedish Cancer Society, CAN 2017/827Swedish Cancer Society, 20 1339 PjF
Available from: 2021-12-20 Created: 2021-12-20 Last updated: 2022-05-13Bibliographically approved
Jamroskovic, J., Doimo, M., Chand, K., Obi, I., Kumar, R., Brännström, K., . . . Sabouri, N. (2020). Quinazoline Ligands Induce Cancer Cell Death through Selective STAT3 Inhibition and G-Quadruplex Stabilization. Journal of the American Chemical Society, 142(6), 2876-2888
Open this publication in new window or tab >>Quinazoline Ligands Induce Cancer Cell Death through Selective STAT3 Inhibition and G-Quadruplex Stabilization
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2020 (English)In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 142, no 6, p. 2876-2888Article in journal (Refereed) Published
Abstract [en]

The signal transducer and activator of transcription 3 (STAT3) protein is a master regulator of most key hallmarks and enablers of cancer, including cell proliferation and the response to DNA damage. G-Quadruplex (G4) structures are four-stranded noncanonical DNA structures enriched at telomeres and oncogenes' promoters. In cancer cells, stabilization of G4 DNAs leads to replication stress and DNA damage accumulation and is therefore considered a promising target for oncotherapy. Here, we designed and synthesized novel quinazoline-based compounds that simultaneously and selectively affect these two well-recognized cancer targets, G4 DNA structures and the STAT3 protein. Using a combination of in vitro assays, NMR, and molecular dynamics simulations, we show that these small, uncharged compounds not only bind to the STAT3 protein but also stabilize G4 structures. In human cultured cells, the compounds inhibit phosphorylation-dependent activation of STAT3 without affecting the antiapoptotic factor STAT1 and cause increased formation of G4 structures, as revealed by the use of a G4 DNA-specific antibody. As a result, treated cells show slower DNA replication, DNA damage checkpoint activation, and an increased apoptotic rate. Importantly, cancer cells are more sensitive to these molecules compared to noncancerous cell lines. This is the first report of a promising class of compounds that not only targets the DNA damage cancer response machinery but also simultaneously inhibits the STAT3-induced cancer cell proliferation, demonstrating a novel approach in cancer therapy.

National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) Atom and Molecular Physics and Optics
Identifiers
urn:nbn:se:umu:diva-169314 (URN)10.1021/jacs.9b11232 (DOI)000514255300025 ()31990532 (PubMedID)2-s2.0-85079045732 (Scopus ID)
Funder
Knut and Alice Wallenberg FoundationSwedish Research CouncilThe Kempe Foundations, SMK-1632Åke Wiberg FoundationSwedish Cancer SocietyVästerbotten County Council, VLL-643451Västerbotten County Council, VLL-832001EU, Horizon 2020, 751474
Available from: 2020-03-31 Created: 2020-03-31 Last updated: 2023-03-24Bibliographically approved
Mason, J., Cumming, J., Eriksson, A. U., Binder, C., Dongre, M., Patthey, C., . . . Öhlund, D.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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