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Löhr, J.-M., Öhlund, D., Söreskog, E., Andersson, E., Vujasinovic, M., Zethraeus, N. & Sund, M. (2024). Can our experience with surveillance for inherited pancreatic cancer help to identify early pancreatic cancer in the general population?. Familial Cancer
Open this publication in new window or tab >>Can our experience with surveillance for inherited pancreatic cancer help to identify early pancreatic cancer in the general population?
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2024 (English)In: Familial Cancer, ISSN 1389-9600, E-ISSN 1573-7292Article, review/survey (Refereed) Epub ahead of print
Abstract [en]

Screening of the general population for cancer is a matter of primary prevention reducing the burden of disease. Whilst this is successful for several cancers including breast, colon and prostate, the situation to screen and hence prevent pancreatic cancer is different. The organ is not as accessible to simple physical exam or biological samples (fecal or blood test). Neither exists a blood test such as PSA that is cost-effective. Reviewing the evidence from screening risk groups for pancreatic cancer, one must conclude that there is no rational at present to screen the general population, for a lack of appropriate tests.

Place, publisher, year, edition, pages
Springer Nature, 2024
Keywords
General population, Incidental finding, Individuals at risk, Pancreatic cancer, Screening, Surveillance
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-222299 (URN)10.1007/s10689-024-00363-6 (DOI)001174923700001 ()38441833 (PubMedID)2-s2.0-85186597174 (Scopus ID)
Funder
Signe and Olof Wallenius FoundationSwedish Cancer Society, 21 1585Swedish Cancer Society, 22 2318Swedish Cancer Society, 19 0273Swedish Cancer Society, 2011/1110Swedish Cancer Society, 2016/634Swedish Cancer Society, 2017/332Swedish Cancer Society, 2017/827Swedish Cancer Society, 20 1339Swedish Research Council, 2016–02990Swedish Research Council, 2019−01690Region Västerbotten, 583411Region Västerbotten, RV-583411Region Västerbotten, RV-549731Region Västerbotten, RV-841551Region Västerbotten, RV-930478Region Västerbotten, RV-930132Region Västerbotten, RV-99607108Region Västerbotten, RV-9960708Region Västerbotten, VLL-837731Region Västerbotten, RV-930167Region Västerbotten, VLL- 643451Region Västerbotten, RV-978812Sjöberg FoundationKnut and Alice Wallenberg FoundationMarianne and Marcus Wallenberg Foundation
Available from: 2024-03-14 Created: 2024-03-14 Last updated: 2024-03-14Bibliographically approved
Löhr, J.-M., Öhlund, D., Söreskog, E., Andersson, E., Vujasinovic, M., Zethraeus, N. & Sund, M. (2024). Can our experience with surveillance for inherited pancreatic cancer help to identify early pancreatic cancer in the general population?. Familial Cancer
Open this publication in new window or tab >>Can our experience with surveillance for inherited pancreatic cancer help to identify early pancreatic cancer in the general population?
Show others...
2024 (English)In: Familial Cancer, ISSN 1389-9600, E-ISSN 1573-7292Article, review/survey (Refereed) Epub ahead of print
Abstract [en]

Screening of the general population for cancer is a matter of primary prevention reducing the burden of disease. Whilst this is successful for several cancers including breast, colon and prostate, the situation to screen and hence prevent pancreatic cancer is different. The organ is not as accessible to simple physical exam or biological samples (fecal or blood test). Neither exists a blood test such as PSA that is cost-effective. Reviewing the evidence from screening risk groups for pancreatic cancer, one must conclude that there is no rational at present to screen the general population, for a lack of appropriate tests.

Place, publisher, year, edition, pages
Springer Nature, 2024
Keywords
General population, Incidental finding, Individuals at risk, Pancreatic cancer, Screening, Surveillance
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-222361 (URN)10.1007/s10689-024-00363-6 (DOI)2-s2.0-85186597174 (Scopus ID)
Available from: 2024-03-15 Created: 2024-03-15 Last updated: 2024-03-15Bibliographically approved
Labori, K. J., Bratlie, S. O., Andersson, B., Angelsen, J.-H., Biörserud, C., Björnsson, B., . . . Lassen, K. (2024). Neoadjuvant FOLFIRINOX versus upfront surgery for resectable pancreatic head cancer (NORPACT-1): a multicentre, randomised, phase 2 trial. The Lancet Gastroenterology & Hepatology, 9(3), 205-217
Open this publication in new window or tab >>Neoadjuvant FOLFIRINOX versus upfront surgery for resectable pancreatic head cancer (NORPACT-1): a multicentre, randomised, phase 2 trial
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2024 (English)In: The Lancet Gastroenterology & Hepatology, ISSN 2468-1253, Vol. 9, no 3, p. 205-217Article in journal (Refereed) Published
Abstract [en]

Background: In patients undergoing resection for pancreatic cancer, adjuvant modified fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) improves overall survival compared with alternative chemotherapy regimens. We aimed to compare the efficacy and safety of neoadjuvant FOLFIRINOX with the standard strategy of upfront surgery in patients with resectable pancreatic ductal adenocarcinoma.

Methods: NORPACT-1 was a multicentre, randomised, phase 2 trial done in 12 hospitals in Denmark, Finland, Norway, and Sweden. Eligible patients were aged 18 years or older, with a WHO performance status of 0 or 1, and had a resectable tumour of the pancreatic head radiologically strongly suspected to be pancreatic adenocarcinoma. Participants were randomly assigned (3:2 before October, 2018, and 1:1 after) to the neoadjuvant FOLFIRINOX group or upfront surgery group. Patients in the neoadjuvant FOLFIRINOX group received four neoadjuvant cycles of FOLFIRINOX (oxaliplatin 85 mg/m2, irinotecan 180 mg/m2, leucovorin 400 mg/m2, and fluorouracil 400 mg/m2 bolus then 2400 mg/m2 over 46 h on day 1 of each 14-day cycle), followed by surgery and adjuvant chemotherapy. Patients in the upfront surgery group underwent surgery and then received adjuvant chemotherapy. Initially, adjuvant chemotherapy was gemcitabine plus capecitabine (gemcitabine 1000 mg/m2 over 30 min on days 1, 8, and 15 of each 28-day cycle and capecitabine 830 mg/m2 twice daily for 3 weeks with 1 week of rest in each 28-day cycle; four cycles in the neoadjuvant FOLFIRINOX group, six cycles in the upfront surgery group). A protocol amendment was subsequently made to permit use of adjuvant modified FOLFIRINOX (oxaliplatin 85 mg/m2, irinotecan 150 mg/m2, leucovorin 400 mg/m2, and fluorouracil 2400 mg/m2 over 46 h on day 1 of each 14-day cycle; eight cycles in the neoadjuvant FOLFIRINOX group, 12 cycles in the upfront surgery group). Randomisation was performed with a computerised algorithm that stratified for each participating centre and used a concealed block size of two to six. Patients, investigators, and study team members were not masked to treatment allocation. The primary endpoint was overall survival at 18 months. Analyses were done in the intention-to-treat (ITT) and per-protocol populations. Safety was assessed in all patients who were randomly assigned and received at least one cycle of neoadjuvant or adjuvant therapy. This trial is registered with ClinicalTrials.gov, NCT02919787, and EudraCT, 2015-001635-21, and is ongoing.

Findings: Between Feb 8, 2017, and April 21, 2021, 77 patients were randomly assigned to receive neoadjuvant FOLFIRINOX and 63 to undergo upfront surgery. All patients were included in the ITT analysis. For the per-protocol analysis, 17 (22%) patients were excluded from the neoadjuvant FOLFIRINOX group (ten did not receive neoadjuvant therapy, four did not have pancreatic ductal adenocarcinoma, and three received another neoadjuvant regimen), and eight (13%) were excluded from the upfront surgery group (seven did not have pancreatic ductal adenocarcinoma and one did not undergo surgical exploration). 61 (79%) of 77 patients in the neoadjuvant FOLFIRINOX group received neoadjuvant therapy. The proportion of patients alive at 18 months by ITT was 60% (95% CI 49–71) in the neoadjuvant FOLFIRINOX group versus 73% (62–84) in the upfront surgery group (p=0·032), and median overall survival by ITT was 25·1 months (95% CI 17·2–34·9) versus 38·5 months (27·6–not reached; hazard ratio [HR] 1·52 [95% CI 1·00–2·33], log-rank p=0·050). The proportion of patients alive at 18 months in per-protocol analysis was 57% (95% CI 46–67) in the neoadjuvant FOLFIRINOX group versus 70% (55–83) in the upfront surgery group (p=0·14), and median overall survival in per-protocol population was 23·0 months (95% CI 16·2–34·9) versus 34·4 months (19·4–not reached; HR 1·46 [95% CI 0·99–2·17], log-rank p=0·058). In the safety population, 42 (58%) of 73 patients in the neoadjuvant FOLFIRINOX group and 19 (40%) of 47 patients in the upfront surgery group had at least one grade 3 or worse adverse event. 63 (82%) of 77 patients in the neoadjuvant group and 56 (89%) of 63 patients in the upfront surgery group had resection (p=0·24). One sudden death of unknown cause and one COVID-19-related death occurred after the first cycle of neoadjuvant FOLFIRINOX. Adjuvant chemotherapy was initiated in 51 (86%) of 59 patients with resected pancreatic ductal adenocarcinoma in the neoadjuvant FOLFIRINOX group and 44 (90%) of 49 patients with resected pancreatic ductal adenocarcinoma in the upfront surgery group (p=0·56). Adjuvant modified FOLFIRINOX was given to 13 (25%) patients in the neoadjuvant FOLFIRINOX group and 19 (43%) patients in the upfront surgery group. During adjuvant chemotherapy, neutropenia (11 [22%] patients in the neoadjuvant FOLFIRINOX group and five [11%] in the upfront surgery group) was the most common grade 3 or worse adverse event.

Interpretation: This phase 2 trial did not show a survival benefit from neoadjuvant FOLFIRINOX in resectable pancreatic ductal adenocarcinoma compared with upfront surgery. Implementation of neoadjuvant FOLFIRINOX was challenging. Future trials on treatment sequencing in resectable pancreatic ductal adenocarcinoma should be biomarker driven.

Place, publisher, year, edition, pages
Elsevier, 2024
National Category
Cancer and Oncology Surgery
Identifiers
urn:nbn:se:umu:diva-221022 (URN)10.1016/S2468-1253(23)00405-3 (DOI)38237621 (PubMedID)2-s2.0-85183761228 (Scopus ID)
Funder
Sjöberg Foundation
Available from: 2024-03-06 Created: 2024-03-06 Last updated: 2024-03-06Bibliographically approved
Deiana, M., Andrés Castán, J. M., Josse, P., Kahsay, A., Sánchez, D. P., Morice, K., . . . Sabouri, N. (2023). A new G-quadruplex-specific photosensitizer inducing genome instability in cancer cells by triggering oxidative DNA damage and impeding replication fork progression. Nucleic Acids Research, 51(12), 6264-6285
Open this publication in new window or tab >>A new G-quadruplex-specific photosensitizer inducing genome instability in cancer cells by triggering oxidative DNA damage and impeding replication fork progression
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2023 (English)In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 51, no 12, p. 6264-6285Article in journal (Refereed) Published
Abstract [en]

Photodynamic therapy (PDT) ideally relies on the administration, selective accumulation and photoactivation of a photosensitizer (PS) into diseased tissues. In this context, we report a new heavy-atom-free fluorescent G-quadruplex (G4) DNA-binding PS, named DBI. We reveal by fluorescence microscopy that DBI preferentially localizes in intraluminal vesicles (ILVs), precursors of exosomes, which are key components of cancer cell proliferation. Moreover, purified exosomal DNA was recognized by a G4-specific antibody, thus highlighting the presence of such G4-forming sequences in the vesicles. Despite the absence of fluorescence signal from DBI in nuclei, light-irradiated DBI-treated cells generated reactive oxygen species (ROS), triggering a 3-fold increase of nuclear G4 foci, slowing fork progression and elevated levels of both DNA base damage, 8-oxoguanine, and double-stranded DNA breaks. Consequently, DBI was found to exert significant phototoxic effects (at nanomolar scale) toward cancer cell lines and tumor organoids. Furthermore, in vivo testing reveals that photoactivation of DBI induces not only G4 formation and DNA damage but also apoptosis in zebrafish, specifically in the area where DBI had accumulated. Collectively, this approach shows significant promise for image-guided PDT.

Place, publisher, year, edition, pages
Oxford University Press, 2023
National Category
Biochemistry and Molecular Biology Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-212227 (URN)10.1093/nar/gkad365 (DOI)000988008500001 ()37191066 (PubMedID)2-s2.0-85164253573 (Scopus ID)
Funder
Swedish Cancer Society, 22 2380 PjSwedish Research Council, VR-MH 2021–02468Knut and Alice Wallenberg Foundation, KAW 2021-0173Swedish Cancer Society, 21 0302 PT 01 HWenner-Gren Foundations, UPD2020-0097Swedish Cancer Society, 20 0827 PjFCancerforskningsfonden i Norrland, LP 22-2312Cancerforskningsfonden i Norrland, LP20 1024 2257Cancerforskningsfonden i Norrland, LP 21–2298Swedish Research Council, 2017-01531Swedish Society of Medicine, SLS-890521Region Västerbotten, RV-930167Sjöberg FoundationKnut and Alice Wallenberg Foundation, KAW 2015.0114Marianne and Marcus Wallenberg Foundation, MMW 2020.0189Swedish Cancer Society, 20 1339 PjF
Available from: 2023-07-21 Created: 2023-07-21 Last updated: 2023-07-21Bibliographically approved
Gonzalez-Castrillon, L. M., Wurmser, M., Öhlund, D. & Wilson, S. I. (2023). Dysregulation of core neurodevelopmental pathways: a common feature of cancers with perineural invasion. Frontiers in Genetics, 14, Article ID 1181775.
Open this publication in new window or tab >>Dysregulation of core neurodevelopmental pathways: a common feature of cancers with perineural invasion
2023 (English)In: Frontiers in Genetics, E-ISSN 1664-8021, Vol. 14, article id 1181775Article in journal (Refereed) Published
Abstract [en]

Background: High nerve density in tumors and metastasis via nerves (perineural invasion—PNI) have been reported extensively in solid tumors throughout the body including pancreatic, head and neck, gastric, prostate, breast, and colorectal cancers. Ablation of tumor nerves results in improved disease outcomes, suggesting that blocking nerve–tumor communication could be a novel treatment strategy. However, the molecular mechanisms underlying this remain poorly understood. Thus, the aim here was to identify molecular pathways underlying nerve–tumor crosstalk and to determine common molecular features between PNI-associated cancers.

Results: Analysis of head and neck (HNSCC), pancreatic, and gastric (STAD) cancer Gene Expression Omnibus datasets was used to identify differentially expressed genes (DEGs). This revealed extracellular matrix components as highly dysregulated. To enrich for pathways associated with PNI, genes previously correlated with PNI in STAD and in 2 HNSCC studies where tumor samples were segregated by PNI status were analyzed. Neurodevelopmental genes were found to be enriched with PNI. In datasets where tumor samples were not segregated by PNI, neurodevelopmental pathways accounted for 12%–16% of the DEGs. Further dysregulation of axon guidance genes was common to all cancers analyzed. By examining paralog genes, a clear pattern emerged where at least one family member from several axon guidance pathways was affected in all cancers examined. Overall 17 different axon guidance gene families were disrupted, including the ephrin–Eph, semaphorin–neuropilin/plexin, and slit–robo pathways. These findings were validated using The Cancer Genome Atlas and cross-referenced to other cancers with a high incidence of PNI including colon, cholangiocarcinoma, prostate, and breast cancers. Survival analysis revealed that the expression levels of neurodevelopmental gene families impacted disease survival.

Conclusion: These data highlight the importance of the tumor as a source of signals for neural tropism and neural plasticity as a common feature of cancer. The analysis supports the hypothesis that dysregulation of neurodevelopmental programs is a common feature associated with PNI. Furthermore, the data suggested that different cancers may have evolved to employ alternative genetic strategies to disrupt the same pathways. Overall, these findings provide potential druggable targets for novel therapies of cancer management and provide multi-cancer molecular biomarkers.

Place, publisher, year, edition, pages
Frontiers Media S.A., 2023
Keywords
bioinformatics, biomarker, cancer, head and neck squamous cell carcinoma, neurodevelopment, pancreatic ductal adenocarcinoma, perineural invasion, stomach adenocarcinoma
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-214621 (URN)10.3389/fgene.2023.1181775 (DOI)2-s2.0-85170839267 (Scopus ID)
Funder
Umeå University, FS 2.1.6-1119-19Knut and Alice Wallenberg Foundation, MMW 2020.0189Marianne and Marcus Wallenberg Foundation, MMW 2020.0189
Available from: 2023-09-26 Created: 2023-09-26 Last updated: 2023-11-20Bibliographically approved
Lidström, T., Cumming, J., Gaur, R., Frängsmyr, L., Pateras, I., Mickert, M. J., . . . Öhlund, D. (2023). Extracellular galectin 4 drives immune evasion and promotes T-cell apoptosis in pancreatic cancer. Cancer immunology research, 11(1), 72-92
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
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
Erice, O., Narayanan, S., Feliu, I., Entrialgo-Cadierno, R., Malinova, A., Vicentini, C., . . . Vicent, S. (2023). LAMC2 regulates key transcriptional and targetable effectors to support pancreatic cancer growth. Clinical Cancer Research, 29(6), 1137-1154
Open this publication in new window or tab >>LAMC2 regulates key transcriptional and targetable effectors to support pancreatic cancer growth
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2023 (English)In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 29, no 6, p. 1137-1154Article in journal (Refereed) Published
Abstract [en]

PURPOSE: The identification of pancreatic ductal adenocarcinoma (PDAC) dysregulated genes may unveil novel molecular targets entering inhibitory strategies. Laminins are emerging as potential targets in PDAC given their role as diagnostic and prognostic markers. Here, we investigated the cellular, functional, and clinical relevance of LAMC2 and its regulated network, with the ultimate goal of identifying potential therapies.

EXPERIMENTAL DESIGN: LAMC2 expression was analyzed in PDAC tissues, a panel of human and mouse cell lines, and a genetically engineered mouse model. Genetic perturbation in 2D, 3D, and in vivo allograft and xenograft models was done. Expression profiling of a LAMC2 network was performed by RNA-sequencing, and publicly available gene expression datasets from experimental and clinical studies examined to query its human relevance. Dual inhibition of pharmacologically targetable LAMC2-regulated effectors was investigated.

RESULTS: LAMC2 was consistently upregulated in human and mouse experimental models as well as in human PDAC specimens, and associated with tumor grade and survival. LAMC2 inhibition impaired cell cycle, induced apoptosis, and sensitized PDAC to MEK1/2 inhibitors (MEK1/2i). A LAMC2-regulated network was featured in PDAC, including both classical and quasi-mesenchymal subtypes, and contained downstream effectors transcriptionally shared by the KRAS signaling pathway. LAMC2 regulated a functional FOSL1-AXL axis via AKT phosphorylation. Furthermore, genetic LAMC2 or pharmacological AXL inhibition elicited a synergistic antiproliferative effect in combination with MEK1/2is that was consistent across 2D and 3D human and mouse PDAC models, including primary patient-derived organoids.

CONCLUSIONS: LAMC2 is a molecular target in PDAC that regulates a transcriptional network that unveils a dual drug combination for cancer treatment.

Place, publisher, year, edition, pages
American Association for Cancer Research (AACR), 2023
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-206023 (URN)10.1158/1078-0432.CCR-22-0794 (DOI)000996642100001 ()36607777 (PubMedID)2-s2.0-85150225593 (Scopus ID)
Available from: 2023-03-28 Created: 2023-03-28 Last updated: 2023-09-05Bibliographically 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
Projects
Targeting Tumor-stromal Interactions in Pancreatic Cancer [2017-01531_VR]; Umeå University; Publications
Lidström, T., Cumming, J., Gaur, R., Frängsmyr, L., Pateras, I., Mickert, M. J., . . . Öhlund, D. (2023). Extracellular galectin 4 drives immune evasion and promotes T-cell apoptosis in pancreatic cancer. Cancer immunology research, 11(1), 72-92Lidström, T. (2022). Immunosuppressive and metastasis-promoting matrisome proteins in pancreatic cancer: the role of galectin 4 and SERPINB5. (Doctoral dissertation). Umeå: Umeå UniversityLidström, T., Patthey, C. & Öhlund, D.Coordination and cooperation of immunosuppressive mechanisms in pancreatic ductal adenocarcinoma.
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-5847-2778

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