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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
Öppna denna publikation i ny flik eller fönster >>Can our experience with surveillance for inherited pancreatic cancer help to identify early pancreatic cancer in the general population?
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2024 (Engelska)Ingår i: Familial Cancer, ISSN 1389-9600, E-ISSN 1573-7292Artikel, forskningsöversikt (Refereegranskat) 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.

Ort, förlag, år, upplaga, sidor
Springer Nature, 2024
Nyckelord
General population, Incidental finding, Individuals at risk, Pancreatic cancer, Screening, Surveillance
Nationell ämneskategori
Cancer och onkologi
Identifikatorer
urn:nbn:se:umu:diva-222299 (URN)10.1007/s10689-024-00363-6 (DOI)001174923700001 ()38441833 (PubMedID)2-s2.0-85186597174 (Scopus ID)
Forskningsfinansiär
Signe och Olof Wallenius StiftelseCancerfonden, 21 1585Cancerfonden, 22 2318Cancerfonden, 19 0273Cancerfonden, 2011/1110Cancerfonden, 2016/634Cancerfonden, 2017/332Cancerfonden, 2017/827Cancerfonden, 20 1339Vetenskapsrådet, 2016–02990Vetenskapsrådet, 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-978812SjöbergstiftelsenKnut och Alice Wallenbergs StiftelseMarianne och Marcus Wallenbergs Stiftelse
Tillgänglig från: 2024-03-14 Skapad: 2024-03-14 Senast uppdaterad: 2024-03-14Bibliografiskt granskad
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
Öppna denna publikation i ny flik eller fönster >>Can our experience with surveillance for inherited pancreatic cancer help to identify early pancreatic cancer in the general population?
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2024 (Engelska)Ingår i: Familial Cancer, ISSN 1389-9600, E-ISSN 1573-7292Artikel, forskningsöversikt (Refereegranskat) 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.

Ort, förlag, år, upplaga, sidor
Springer Nature, 2024
Nyckelord
General population, Incidental finding, Individuals at risk, Pancreatic cancer, Screening, Surveillance
Nationell ämneskategori
Cancer och onkologi
Identifikatorer
urn:nbn:se:umu:diva-222361 (URN)10.1007/s10689-024-00363-6 (DOI)2-s2.0-85186597174 (Scopus ID)
Tillgänglig från: 2024-03-15 Skapad: 2024-03-15 Senast uppdaterad: 2024-03-15Bibliografiskt granskad
Borgmästars, E., Jacobson, S., Simm, M., Johansson, M., Billing, O., Lundin, C., . . . Sund, M. (2024). Metabolomics for early pancreatic cancer detection in plasma samples from a Swedish prospective population-based biobank. Journal of Gastrointestinal Oncology, 15(2), 755-767
Öppna denna publikation i ny flik eller fönster >>Metabolomics for early pancreatic cancer detection in plasma samples from a Swedish prospective population-based biobank
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2024 (Engelska)Ingår i: Journal of Gastrointestinal Oncology, ISSN 2078-6891, E-ISSN 2219-679X, Vol. 15, nr 2, s. 755-767Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Background: Pancreatic ductal adenocarcinoma (pancreatic cancer) is often detected at late stages resulting in poor overall survival. To improve survival, more patients need to be diagnosed early when curative surgery is feasible. We aimed to identify circulating metabolites that could be used as early pancreatic cancer biomarkers.

Methods: We performed metabolomics by liquid and gas chromatography-mass spectrometry in plasma samples from 82 future pancreatic cancer patients and 82 matched healthy controls within the Northern Sweden Health and Disease Study (NSHDS). Logistic regression was used to assess univariate associations between metabolites and pancreatic cancer risk. Least absolute shrinkage and selection operator (LASSO) logistic regression was used to design a metabolite-based risk score. We used receiver operating characteristic (ROC) analyses to assess the discriminative performance of the metabolite-based risk score.

Results: Among twelve risk-associated metabolites with a nominal P value <0.05, we defined a risk score of three metabolites [indoleacetate, 3-hydroxydecanoate (10:0-OH), and retention index (RI): 2,745.4] using LASSO. A logistic regression model containing these three metabolites, age, sex, body mass index (BMI), smoking status, sample date, fasting status, and carbohydrate antigen 19-9 (CA 19-9) yielded an internal area under curve (AUC) of 0.784 [95% confidence interval (CI): 0.714–0.854] compared to 0.681 (95% CI: 0.597–0.764) for a model without these metabolites (P value =0.007). Seventeen metabolites were significantly associated with pancreatic cancer survival [false discovery rate (FDR) <0.1].

Conclusions: Indoleacetate, 3-hydroxydecanoate (10:0-OH), and RI: 2,745.4 were identified as the top candidate biomarkers for early detection. However, continued efforts are warranted to determine the usefulness of these metabolites as early pancreatic cancer biomarkers.

Ort, förlag, år, upplaga, sidor
AME Publishing Company, 2024
Nyckelord
biomarkers, hyperglycemia, Pancreatic neoplasms, risk, survival
Nationell ämneskategori
Cancer och onkologi
Identifikatorer
urn:nbn:se:umu:diva-224962 (URN)10.21037/jgo-23-930 (DOI)2-s2.0-85192826642 (Scopus ID)
Forskningsfinansiär
Umeå universitetCancerfonden, 19 0273Cancerfonden, 2017-557Cancerfonden, CAN 2017/332Cancerfonden, CAN 2017/827Vetenskapsrådet, 2019-01690Vetenskapsrådet, 2016-02990Vetenskapsrådet, 2017-01531Region Västerbotten, RV-583411Region Västerbotten, RV-549731Region Västerbotten, RV-841551Region Västerbotten, RV-930167Region Västerbotten, VLL-643451
Tillgänglig från: 2024-05-27 Skapad: 2024-05-27 Senast uppdaterad: 2024-05-27Bibliografiskt granskad
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
Öppna denna publikation i ny flik eller fönster >>Neoadjuvant FOLFIRINOX versus upfront surgery for resectable pancreatic head cancer (NORPACT-1): a multicentre, randomised, phase 2 trial
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2024 (Engelska)Ingår i: The Lancet Gastroenterology & Hepatology, ISSN 2468-1253, Vol. 9, nr 3, s. 205-217Artikel i tidskrift (Refereegranskat) 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.

Ort, förlag, år, upplaga, sidor
Elsevier, 2024
Nationell ämneskategori
Cancer och onkologi Kirurgi
Identifikatorer
urn:nbn:se:umu:diva-221022 (URN)10.1016/S2468-1253(23)00405-3 (DOI)38237621 (PubMedID)2-s2.0-85183761228 (Scopus ID)
Forskningsfinansiär
Sjöbergstiftelsen
Tillgänglig från: 2024-03-06 Skapad: 2024-03-06 Senast uppdaterad: 2024-03-06Bibliografiskt granskad
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
Öppna denna publikation i ny flik eller fönster >>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 (Engelska)Ingår i: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 51, nr 12, s. 6264-6285Artikel i tidskrift (Refereegranskat) 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.

Ort, förlag, år, upplaga, sidor
Oxford University Press, 2023
Nationell ämneskategori
Biokemi och molekylärbiologi Cell- och molekylärbiologi
Identifikatorer
urn:nbn:se:umu:diva-212227 (URN)10.1093/nar/gkad365 (DOI)000988008500001 ()37191066 (PubMedID)2-s2.0-85164253573 (Scopus ID)
Forskningsfinansiär
Cancerfonden, 22 2380 PjVetenskapsrådet, VR-MH 2021–02468Knut och Alice Wallenbergs Stiftelse, KAW 2021-0173Cancerfonden, 21 0302 PT 01 HWenner-Gren Stiftelserna, UPD2020-0097Cancerfonden, 20 0827 PjFCancerforskningsfonden i Norrland, LP 22-2312Cancerforskningsfonden i Norrland, LP20 1024 2257Cancerforskningsfonden i Norrland, LP 21–2298Vetenskapsrådet, 2017-01531Svenska läkaresällskapet, SLS-890521Region Västerbotten, RV-930167SjöbergstiftelsenKnut och Alice Wallenbergs Stiftelse, KAW 2015.0114Marianne och Marcus Wallenbergs Stiftelse, MMW 2020.0189Cancerfonden, 20 1339 PjF
Tillgänglig från: 2023-07-21 Skapad: 2023-07-21 Senast uppdaterad: 2023-07-21Bibliografiskt granskad
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.
Öppna denna publikation i ny flik eller fönster >>Dysregulation of core neurodevelopmental pathways: a common feature of cancers with perineural invasion
2023 (Engelska)Ingår i: Frontiers in Genetics, E-ISSN 1664-8021, Vol. 14, artikel-id 1181775Artikel i tidskrift (Refereegranskat) 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.

Ort, förlag, år, upplaga, sidor
Frontiers Media S.A., 2023
Nyckelord
bioinformatics, biomarker, cancer, head and neck squamous cell carcinoma, neurodevelopment, pancreatic ductal adenocarcinoma, perineural invasion, stomach adenocarcinoma
Nationell ämneskategori
Cancer och onkologi
Identifikatorer
urn:nbn:se:umu:diva-214621 (URN)10.3389/fgene.2023.1181775 (DOI)2-s2.0-85170839267 (Scopus ID)
Forskningsfinansiär
Umeå universitet, FS 2.1.6-1119-19Knut och Alice Wallenbergs Stiftelse, MMW 2020.0189Marianne och Marcus Wallenbergs Stiftelse, MMW 2020.0189
Tillgänglig från: 2023-09-26 Skapad: 2023-09-26 Senast uppdaterad: 2023-11-20Bibliografiskt granskad
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
Öppna denna publikation i ny flik eller fönster >>Extracellular galectin 4 drives immune evasion and promotes T-cell apoptosis in pancreatic cancer
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2023 (Engelska)Ingår i: Cancer immunology research, ISSN 2326-6066, Vol. 11, nr 1, s. 72-92Artikel i tidskrift (Refereegranskat) 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. 

Ort, förlag, år, upplaga, sidor
American Association for Cancer Research, 2023
Nyckelord
Galectin 4, pancreatic cancer, immunosuppression, extracellular matrix, drug target
Nationell ämneskategori
Cancer och onkologi
Forskningsämne
immunologi; medicin; onkologi
Identifikatorer
urn:nbn:se:umu:diva-201042 (URN)10.1158/2326-6066.CIR-21-1088 (DOI)36478037 (PubMedID)2-s2.0-85145492684 (Scopus ID)
Forskningsfinansiär
Stiftelsen för internationalisering av högre utbildning och forskning (STINT), PT2015-6432Cancerfonden, AMP17-877, LP18-2202, LP20-2257, LP 21-2298Vetenskapsrådet, 2017-01531Kempestiftelserna, JCK-1301, SMK-1765Svenska läkaresällskapet, SLS-890521, SLS-786661, SLS-691681, SLS-591551Västerbottens läns landsting, RV-930167, VLL-643451, VLL-832001SjöbergstiftelsenKnut och Alice Wallenbergs StiftelseMarianne och Marcus Wallenbergs Stiftelse, MMW 2020.0189Cancerfonden, CAN 2017/332, CAN 2017/827, 20 1339 PjFCancerfonden, AMP-18-919Knut och Alice Wallenbergs Stiftelse
Anmärkning

Originally included in thesis in manuscript form. 

Tillgänglig från: 2022-11-16 Skapad: 2022-11-16 Senast uppdaterad: 2023-10-18Bibliografiskt granskad
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.
Öppna denna publikation i ny flik eller fönster >>Key aspects for conception and construction of co-culture models of tumor-stroma interactions
2023 (Engelska)Ingår i: Frontiers in Bioengineering and Biotechnology, E-ISSN 2296-4185, Vol. 11, artikel-id 1150764Artikel, forskningsöversikt (Refereegranskat) 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.

Ort, förlag, år, upplaga, sidor
Frontiers Media S.A., 2023
Nyckelord
cancer associated fibroblasts, cell culture models, co-culture, organoid, tumor-stroma interactions
Nationell ämneskategori
Medicinsk bioteknologi (med inriktning mot cellbiologi (inklusive stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci) Cancer och onkologi
Identifikatorer
urn:nbn:se:umu:diva-208065 (URN)10.3389/fbioe.2023.1150764 (DOI)000975436300001 ()37091337 (PubMedID)2-s2.0-85153519815 (Scopus ID)
Forskningsfinansiär
Cancerforskningsfonden i Norrland, LP20-2257Cancerforskningsfonden i Norrland, LP 21-2298Cancerforskningsfonden i Norrland, LP22-2332Vetenskapsrådet, 2017-01531Vetenskapsrådet, 2022-00855Svenska läkaresällskapet, SLS-890521Region Västerbotten, RV-930167Region Västerbotten, RV-978812Knut och Alice Wallenbergs StiftelseMarianne och Marcus Wallenbergs Stiftelse, MMW 2020.0189Cancerfonden, 20 1339 PjF
Tillgänglig från: 2023-05-29 Skapad: 2023-05-29 Senast uppdaterad: 2023-05-29Bibliografiskt granskad
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
Öppna denna publikation i ny flik eller fönster >>LAMC2 regulates key transcriptional and targetable effectors to support pancreatic cancer growth
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2023 (Engelska)Ingår i: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 29, nr 6, s. 1137-1154Artikel i tidskrift (Refereegranskat) 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.

Ort, förlag, år, upplaga, sidor
American Association for Cancer Research (AACR), 2023
Nationell ämneskategori
Cancer och onkologi
Identifikatorer
urn:nbn:se:umu:diva-206023 (URN)10.1158/1078-0432.CCR-22-0794 (DOI)000996642100001 ()36607777 (PubMedID)2-s2.0-85150225593 (Scopus ID)
Tillgänglig från: 2023-03-28 Skapad: 2023-03-28 Senast uppdaterad: 2023-09-05Bibliografiskt granskad
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.
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2023 (Engelska)Ingår i: European Journal of Medicinal Chemistry, ISSN 0223-5234, E-ISSN 1768-3254, Vol. 248, artikel-id 115103Artikel i tidskrift (Refereegranskat) 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.

Ort, förlag, år, upplaga, sidor
Elsevier, 2023
Nationell ämneskategori
Läkemedelskemi
Identifikatorer
urn:nbn:se:umu:diva-202112 (URN)10.1016/j.ejmech.2023.115103 (DOI)000922160800001 ()2-s2.0-85146280645 (Scopus ID)
Forskningsfinansiär
Kempestiftelserna, SMK-1632Vetenskapsrådet, 2017–05235Vetenskapsrådet, 2017- 01531Sveriges läkarförbund, SLS-890521Region Västerbotten, RV-930167Knut och Alice Wallenbergs StiftelseMarianne och Marcus Wallenbergs Stiftelse, 2020.0189Cancerfonden, 20 1339 PjFCancerforskningsfonden i Norrland, LP 21–2298Cancerforskningsfonden i Norrland, LP 22–2332
Anmärkning

Originally included in thesis in manuscript form.

Tillgänglig från: 2023-01-02 Skapad: 2023-01-02 Senast uppdaterad: 2023-09-05Bibliografiskt granskad
Projekt
Tumörstromat som läkemedelsmål vid pankreascancer [2017-01531_VR]; Umeå universitet; Publikationer
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.
Organisationer
Identifikatorer
ORCID-id: ORCID iD iconorcid.org/0000-0002-5847-2778

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