umu.sePublications
Change search
Link to record
Permanent link

Direct link
BETA
Publications (10 of 17) Show all publications
Franklin, O., Billing, O., Öhlund, D., Berglund, A., Herdenberg, C., Wang, W., . . . Sund, M. (2019). Novel prognostic markers within the CD44-stromal ligand network in pancreatic cancer. Journal of Pathology, 5(2), 130-141
Open this publication in new window or tab >>Novel prognostic markers within the CD44-stromal ligand network in pancreatic cancer
Show others...
2019 (English)In: Journal of Pathology, ISSN 0022-3417, E-ISSN 1096-9896, Vol. 5, no 2, p. 130-141Article in journal (Refereed) Published
Abstract [en]

The dense stroma in pancreatic cancer tumours is rich in secreted extracellular matrix proteins and proteoglycans. Secreted hyaluronan, osteopontin and type IV collagen sustain oncogenic signalling by interactions with CD44s and its variant isoform CD44v6 on cancer cell membranes. Although well established in animal and in vitro models, this oncogenic CD44-stromal ligand network is less explored in human cancer. Here, we use a pancreatic cancer tissue microarray from 69 primary tumours and 37 metastatic lymph nodes and demonstrate that high tumour cell expression of CD44s and, surprisingly, low stromal deposition of osteopontin correlate with poor survival independent of established prognostic factors for pancreatic cancer. High stromal expression of hyaluronan was a universal trait of both primary tumours and metastatic lymph nodes. However, hyaluronan species of different molecular mass are known to function differently in pancreatic cancer biology and immunohistochemistry cannot distinguish between them. Using gas-phase electrophoretic molecular mobility analysis, we uncover a shift towards high molecular mass hyaluronan in pancreatic cancer tissue compared to normal pancreas and at a transcriptional level, we find that hyaluronan synthesising HAS2 correlates positively with CD44. The resulting prediction that high molecular mass hyaluronan would then correlate with poor survival in pancreatic cancer was confirmed in serum samples, where we demonstrate that hyaluronan >27 kDa measured before surgery is an independent predictor of postoperative survival. Our findings confirm the prognostic value of CD44 tissue expression and highlight osteopontin tissue expression and serum high molecular mass hyaluronan as novel prognostic markers in pancreatic cancer.

Place, publisher, year, edition, pages
John Wiley & Sons, 2019
Keywords
CD44, biomarkers, hyaluronan, osteopontin, pancreatic cancer, type IV collagen
National Category
Cancer and Oncology
Research subject
Oncology
Identifiers
urn:nbn:se:umu:diva-154564 (URN)10.1002/cjp2.122 (DOI)000465218700006 ()30456933 (PubMedID)2-s2.0-85064472279 (Scopus ID)
Available from: 2018-12-19 Created: 2018-12-19 Last updated: 2019-05-20Bibliographically approved
Tian, C., Clauser, K. R., Öhlund, D., Rickelt, S., Huang, Y., Gupta, M., . . . Hynes, R. O. (2019). Proteomic analyses of ECM during pancreatic ductal adenocarcinoma progression reveal different contributions by tumor and stromal cells. Proceedings of the National Academy of Sciences of the United States of America, 116(39), 19609-19618
Open this publication in new window or tab >>Proteomic analyses of ECM during pancreatic ductal adenocarcinoma progression reveal different contributions by tumor and stromal cells
Show others...
2019 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 116, no 39, p. 19609-19618Article in journal (Refereed) Published
Abstract [en]

Pancreatic ductal adenocarcinoma (PDAC) has prominent extracellular matrix (ECM) that compromises treatments yet cannot be nonselectively disrupted without adverse consequences. ECM of PDAC, despite the recognition of its importance, has not been comprehensively studied in patients. In this study, we used quantitative mass spectrometry (MS)-based proteomics to characterize ECM proteins in normal pancreas and pancreatic intraepithelial neoplasia (PanIN)- and PDAC-bearing pancreas from both human patients and mouse genetic models, as well as chronic pancreatitis patient samples. We describe detailed changes in both abundance and complexity of matrisome proteins in the course of PDAC progression. We reveal an early upregulated group of matrisome proteins in PanIN, which are further upregulated in PDAC, and we uncover notable similarities in matrix changes between pancreatitis and PDAC. We further assigned cellular origins to matrisome proteins by performing MS on multiple lines of human-to-mouse xenograft tumors. We found that, although stromal cells produce over 90% of the ECM mass, elevated levels of ECM proteins derived from the tumor cells, but not those produced exclusively by stromal cells, tend to correlate with poor patient survival. Furthermore, distinct pathways were implicated in regulating expression of matrisome proteins in cancer cells and stromal cells. We suggest that, rather than global suppression of ECM production, more precise ECM manipulations, such as targeting tumor-promoting ECM proteins and their regulators in cancer cells, could be more effective therapeutically.

Place, publisher, year, edition, pages
National Academy of Sciences, 2019
Keywords
PanIN, pancreatitis, PDAC, ECM
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-164047 (URN)10.1073/pnas.1908626116 (DOI)000487532900060 ()31484774 (PubMedID)
Available from: 2019-10-15 Created: 2019-10-15 Last updated: 2019-10-15Bibliographically approved
Neesse, A., Bauer, C. A., Öhlund, D., Lauth, M., Buchholz, M., Michl, P., . . . Gress, T. M. (2019). Stromal biology and therapy in pancreatic cancer: ready for clinical translation?. Gut, 68(1), 159-171
Open this publication in new window or tab >>Stromal biology and therapy in pancreatic cancer: ready for clinical translation?
Show others...
2019 (English)In: Gut, ISSN 0017-5749, E-ISSN 1468-3288, Vol. 68, no 1, p. 159-171Article in journal (Refereed) Published
Abstract [en]

Pancreatic ductal adenocarcinoma (PDA) is notoriously aggressive and hard to treat. The tumour microenvironment (TME) in PDA is highly dynamic and has been found to promote tumour progression, metastasis niche formation and therapeutic resistance. Intensive research of recent years has revealed an incredible heterogeneity and complexity of the different components of the TME, including cancer-associated fibroblasts, immune cells, extracellular matrix components, tumour vessels and nerves. It has been hypothesised that paracrine interactions between neoplastic epithelial cells and TME compartments may result in either tumour-promoting or tumour-restraining consequences. A better preclinical understanding of such complex and dynamic network systems is required to develop more powerful treatment strategies for patients. Scientific activity and the number of compelling findings has virtually exploded during recent years. Here, we provide an update of the most recent findings in this area and discuss their translational and clinical implications for basic scientists and clinicians alike.

Place, publisher, year, edition, pages
BMJ Publishing Group Ltd, 2019
National Category
Gastroenterology and Hepatology Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-166519 (URN)10.1136/gutjnl-2018-316451 (DOI)000455727900022 ()30177543 (PubMedID)
Available from: 2019-12-17 Created: 2019-12-17 Last updated: 2019-12-17Bibliographically approved
Franklin, O., Jonsson, P., Billing, O., Lundberg, E., Öhlund, D., Nyström, H., . . . Sund, M. (2018). Plasma micro-RNA alterations appear late in pancreatic cancer. Annals of Surgery, 267(4), 775-781
Open this publication in new window or tab >>Plasma micro-RNA alterations appear late in pancreatic cancer
Show others...
2018 (English)In: Annals of Surgery, ISSN 0003-4932, E-ISSN 1528-1140, Vol. 267, no 4, p. 775-781Article in journal (Refereed) Published
Abstract [en]

Objectives: The aim of this research was to study whether plasma microRNAs (miRNA) can be used for early detection of pancreatic cancer (PC) by analyzing prediagnostic plasma samples collected before a PC diagnosis. Background: PC has a poor prognosis due to late presenting symptoms and early metastasis. Circulating miRNAs are altered in PC at diagnosis but have not been evaluated in a prediagnostic setting. Methods: We first performed an initial screen using a panel of 372 miRNAs in a retrospective case-control cohort that included early-stage PC patients and healthy controls. Significantly altered miRNAs at diagnosis were then measured in an early detection case-control cohort wherein plasma samples in the cases are collected before a PC diagnosis. Carbohydrate antigen 19–9 (Ca 19–9) levels were measured in all samples for comparison. Results: Our initial screen, including 23 stage I-II PC cases and 22 controls, revealed 15 candidate miRNAs that were differentially expressed in plasma samples at PC diagnosis. We combined all 15 miRNAs into a multivariate statistical model, which outperformed Ca 19–9 in receiver-operating characteristics analysis. However, none of the candidate miRNAs, individually or in combination, were significantly altered in prediagnostic plasma samples from 67 future PC patients compared with 132 matched controls. In comparison, Ca 19–9 levels were significantly higher in the cases at <5 years before diagnosis. Conclusion: Plasma miRNAs are altered in PC patients at diagnosis, but the candidate miRNAs found in this study appear late in the course of the disease and cannot be used for early detection of the disease.

Keywords
blood samples, early detection, micro-RNA, miRNA, pancreatic cancer
National Category
Clinical Laboratory Medicine Chemical Sciences
Identifiers
urn:nbn:se:umu:diva-127998 (URN)10.1097/SLA.0000000000002124 (DOI)000435846900046 ()28425921 (PubMedID)2-s2.0-85044257717 (Scopus ID)
Note

Originally included in thesis in manuscript form.

Available from: 2016-11-21 Created: 2016-11-21 Last updated: 2018-09-27Bibliographically approved
Morin, E., Sjöberg, E., Tjomsland, V., Testini, C., Lindskog, C., Franklin, O., . . . Claesson-Welsh, L. (2018). VEGF receptor-2/neuropilin 1 trans-complex formation between endothelial and tumor cells is an independent predictor of pancreatic cancer survival. Journal of Pathology, 246(3), 311-322
Open this publication in new window or tab >>VEGF receptor-2/neuropilin 1 trans-complex formation between endothelial and tumor cells is an independent predictor of pancreatic cancer survival
Show others...
2018 (English)In: Journal of Pathology, ISSN 0022-3417, E-ISSN 1096-9896, Vol. 246, no 3, p. 311-322Article in journal (Refereed) Published
Abstract [en]

Unstable and dysfunctional tumor vasculature promotes cancer progression and spread. Signal transduction by the pro-angiogenic vascular endothelial growth factor (VEGF) receptor-2 (VEGFR2) is modulated by VEGFA-dependent complex formation with neuropilin 1 (NRP1). NRP1 expressed on tumor cells can form VEGFR2/NRP1 trans-complexes between tumor cells and endothelial cells which arrests VEGFR2 on the endothelial surface, thus interfering with productive VEGFR2 signaling. In mouse fibrosarcoma, VEGFR2/NRP1 trans-complexes correlated with reduced tumor vessel branching and reduced tumor cell proliferation. Pancreatic ductal adenocarcinoma (PDAC) strongly expressed NRP1 on both tumor cells and endothelial cells, in contrast to other common cancer forms. Using proximity ligation assay, VEGFR2/NRP1 trans-complexes were identified in human PDAC tumor tissue, and its presence was associated with reduced tumor vessel branching, reduced tumor cell proliferation, and improved patient survival after adjusting for other known survival predictors. We conclude that VEGFR2/NRP1 trans-complex formation is an independent predictor of PDAC patient survival. 

Place, publisher, year, edition, pages
John Wiley & Sons, 2018
Keywords
VEGF, neuropilin 1, pancreatic adenocarcinoma, trans-complex, branching
National Category
Cell and Molecular Biology Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:umu:diva-152971 (URN)10.1002/path.5141 (DOI)000447161600007 ()30027561 (PubMedID)
Funder
Swedish Research Council, 2015-02375Swedish Cancer Society, CAN2016/578Knut and Alice Wallenberg Foundation, KAW 2015.0030Knut and Alice Wallenberg Foundation, KAW 2015.0275
Available from: 2018-11-01 Created: 2018-11-01 Last updated: 2018-11-01Bibliographically approved
Öhlund, D. (2017). Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer. Journal of Experimental Medicine, 214(3), 579-596
Open this publication in new window or tab >>Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer
2017 (English)In: Journal of Experimental Medicine, ISSN 0022-1007, E-ISSN 1540-9538, Vol. 214, no 3, p. 579-596Article in journal (Refereed) Published
Abstract [en]

Pancreatic stellate cells (PSCs) differentiate into cancer-associated fibroblasts (CAFs) that produce desmoplastic stroma, thereby modulating disease progression and therapeutic response in pancreatic ductal adenocarcinoma (PDA). However, it is unknown whether CAFs uniformly carry out these tasks or if subtypes of CAFs with distinct phenotypes in PDA exist. We identified a CAF subpopulation with elevated expression of a-smooth muscle actin (alpha SMA) located immediately adjacent to neoplastic cells in mouse and human PDA tissue. We recapitulated this finding in co-cultures of murine PSCs and PDA organoids, and demonstrated that organoid-activated CAFs produced desmoplastic stroma. The co-cultures showed cooperative interactions and revealed another distinct subpopulation of CAFs, located more distantly from neoplastic cells, which lacked elevated aSMA expression and instead secreted IL6 and additional inflammatory mediators. These findings were corroborated in mouse and human PDA tissue, providing direct evidence for CAF heterogeneity in PDA tumor biology with implications for disease etiology and therapeutic development.

National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-132073 (URN)10.1084/jem.20162024 (DOI)000395828600002 ()28232471 (PubMedID)
Available from: 2017-03-02 Created: 2017-03-02 Last updated: 2018-06-09Bibliographically approved
Chio, I. I., Jafarnejad, S. M., Ponz-Sarvise, M., Park, Y., Rivera, K., Palm, W., . . . Tuveson, D. A. (2016). NRF2 Promotes Tumor Maintenance by Modulating mRNA Translation in Pancreatic Cancer. Cell, 166(4), 936-976
Open this publication in new window or tab >>NRF2 Promotes Tumor Maintenance by Modulating mRNA Translation in Pancreatic Cancer
Show others...
2016 (English)In: Cell, ISSN 0092-8674, E-ISSN 1097-4172, Vol. 166, no 4, p. 936-976Article in journal (Refereed) Published
Abstract [en]

Pancreatic cancer is a deadly malignancy that lacks effective therapeutics. We previously reported that oncogenic Kras induced the redox master regulator Nfe2l2/Nrf2 to stimulate pancreatic and lung cancer initiation. Here, we show that NRF2 is necessary to maintain pancreatic cancer proliferation by regulating mRNA translation. Specifically, loss of NRF2 led to defects in autocrine epidermal growth factor receptor (EGFR) signaling and oxidation of specific translational regulatory proteins, resulting in impaired cap-dependent and cap-independent mRNA translation in pancreatic cancer cells. Combined targeting of the EGFR effector AKT and the glutathione antioxidant pathway mimicked Nrf2 ablation to potently inhibit pancreatic cancer ex vivo and in vivo, representing a promising synthetic lethal strategy for treating the disease.

National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-130637 (URN)10.1016/j.cell.2016.06.056 (DOI)000382258700018 ()27477511 (PubMedID)
Available from: 2017-01-26 Created: 2017-01-26 Last updated: 2018-06-09Bibliographically approved
Franklin, O., Öhlund, D., Lundin, C., Öman, M., Naredi, P., Wang, W. & Sund, M. (2015). Combining conventional and stroma-derived tumour markers in pancreatic ductal adenocarcinoma. Cancer Biomarkers, 15(1), 1-10
Open this publication in new window or tab >>Combining conventional and stroma-derived tumour markers in pancreatic ductal adenocarcinoma
Show others...
2015 (English)In: Cancer Biomarkers, ISSN 1574-0153, Vol. 15, no 1, p. 1-10Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: A lack of disease-specific symptoms and good tumour markers makes early detection and diagnosis of pancreatic ductal adenocarcinoma (PDAC) challenging. OBJECTIVE: To analyse the tissue expression and circulating levels of four stroma-derived substances (type IV collagen, endostatin/type XVIII collagen, osteopontin and tenascin C) and four conventional tumour markers (CA 19-9, TPS, CEA and Ca 125) in a PDAC cohort.

METHODS: Tissue expression of markers in normal pancreas and PDAC tissue was analysed with immunofluorescence. Plasma concentrations of markers were measured before and after surgery. Patients with non-malignant disorders served as controls.

RESULTS: The conventional and stromal substances were expressed in the cancer cell compartment and the stroma, respectively. Although most patients had increased levels of many markers before surgery, 2/12 (17%) of patients had normal levels of Ca 19-9 at this stage. High preoperative endostatin/type XVIII collagen, and postoperative type IV collagen was associated with short survival. Neither the pre-nor postoperative levels of TPS, Ca 125 or CA 19-9 were associated to survival.

CONCLUSIONS: PDAC is characterized by an abundant stroma. These initial observations indicate that the stroma can be a source of PDAC tumour markers that are found in different compartments of the cancer, thus reflecting different aspects of tumour biology.

Place, publisher, year, edition, pages
IOS Press, 2015
Keywords
Pancreatic ductal adenocarcinoma (PDAC), tumour markers, stroma, type IV collagen, type XVIII llagen, endostatin, osteopontin, tenascin C, TPS, Ca 125, Ca 19-9, CEA
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-97877 (URN)10.3233/CBM-140430 (DOI)000346079800001 ()
Available from: 2015-01-16 Created: 2015-01-08 Last updated: 2018-06-07Bibliographically approved
Boj, S. F., Hwang, C.-I., Baker, L. A., Chio, I. I., Engle, D. D., Corbo, V., . . . Tuveson, D. A. (2015). Organoid models of human and mouse ductal pancreatic cancer. Cell, 160(1-2), 324-338
Open this publication in new window or tab >>Organoid models of human and mouse ductal pancreatic cancer
Show others...
2015 (English)In: Cell, ISSN 0092-8674, E-ISSN 1097-4172, Vol. 160, no 1-2, p. 324-338Article in journal (Refereed) Published
Abstract [en]

Pancreatic cancer is one of the most lethal malignancies due to its late diagnosis and limited response to treatment. Tractable methods to identify and interrogate pathways involved in pancreatic tumorigenesis are urgently needed. We established organoid models from normal and neoplastic murine and human pancreas tissues. Pancreatic organoids can be rapidly generated from resected tumors and biopsies, survive cryopreservation, and exhibit ductal- and disease-stage-specific characteristics. Orthotopically transplanted neoplastic organoids recapitulate the full spectrum of tumor development by forming early-grade neoplasms that progress to locally invasive and metastatic carcinomas. Due to their ability to be genetically manipulated, organoids are a platform to probe genetic cooperation. Comprehensive transcriptional and proteomic analyses of murine pancreatic organoids revealed genes and pathways altered during disease progression. The confirmation of many of these protein changes in human tissues demonstrates that organoids are a facile model system to discover characteristics of this deadly malignancy.

Place, publisher, year, edition, pages
Cell press, 2015
Keywords
acinar-cell transdifferentiation, in-vitro expansion, oncogenic kras, expression profiles, progenitor cells, adenocarcinoma, mice, neoplasia, promotes, identification
National Category
Surgery Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-110301 (URN)10.1016/j.cell.2014.12.021 (DOI)000347923200028 ()25557080 (PubMedID)
Available from: 2015-10-20 Created: 2015-10-20 Last updated: 2018-06-07Bibliographically approved
Öhlund, D., Elyada, E. & Tuveson, D. (2014). Fibroblast heterogeneity in the cancer wound. Journal of Experimental Medicine, 211(8), 1503-1523
Open this publication in new window or tab >>Fibroblast heterogeneity in the cancer wound
2014 (English)In: Journal of Experimental Medicine, ISSN 0022-1007, E-ISSN 1540-9538, Vol. 211, no 8, p. 1503-1523Article, review/survey (Refereed) Published
Abstract [en]

Fibroblasts regulate the structure and function of healthy tissues, participate transiently in tissue repair after acute inflammation, and assume an aberrant stimulatory role during chronic inflammatory states including cancer. Such cancer-associated fibroblasts (CAFs) modulate the tumor microenvironment and influence the behavior of neoplastic cells in either a tumor-promoting or tumor-inhibiting manner. These pleiotropic functions highlight the inherent plasticity of fibroblasts and may provide new avenues to understand and therapeutically intervene in malignancies. We discuss the emerging themes of CAF biology in the context of tumorigenesis and therapy.

National Category
Surgery
Identifiers
urn:nbn:se:umu:diva-102774 (URN)10.1084/jem.20140692 (DOI)25071162 (PubMedID)
Available from: 2015-05-04 Created: 2015-05-04 Last updated: 2018-06-07Bibliographically approved
Projects
Targeting Tumor-stromal Interactions in Pancreatic Cancer [2017-01531_VR]; Umeå University
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-5847-2778

Search in DiVA

Show all publications