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  • 1.
    Kolan, Shrikant S.
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Immunologi/immunkemi.
    Lidström, Tommy
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Immunologi/immunkemi.
    Björk, Karl
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Immunologi/immunkemi.
    Hultdin, Magnus
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    Forsell, Mattias
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Immunologi/immunkemi.
    Modulation of lymphoma growth by a selective serotonin receptor antagonist2017Ingår i: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 86, nr 4, s. 343-343Artikel i tidskrift (Övrigt vetenskapligt)
    Abstract [en]

    The mitogenic neurotransmitter, serotonin (5‐HT) acts as a growth factor for different types of non‐tumoral cells (e.g. vascular smooth muscle cells) and tumor cells (e.g. pancreatic carcinoid cells). The 5‐HT1A is a prototype receptor of 5‐HT1 family and as a G‐protein coupled receptor (GPCR), it exerts inhibitory action through Gi/o subunits and activating response via βγ subunits. 5‐HT1A receptors have long been implicated in the treatment of anxiety and depressive disorders. Apart from its role in neuropsychiatric diseases, 5‐HT1A receptor mediated signaling is important for T and B cell proliferation since blocking of the receptor has been linked to a reduced in vitro proliferative response after mitogenic stimulation. Here, we investigated the phenotypical and molecular effects of serotonin signaling by treating human B cell‐derived lymphoma cell lines with a selective 5‐HT1A antagonist. Our data show that repeated treatments with the 5‐HT1A antagonist resulted in significantly reduced proliferation in human B‐derived lymphoma cell lines. We demonstrate that the block in proliferation was associated with induction of apoptosis, DNA damage and morphological alterations of surviving cells. We also provide evidence that treatment of lymphoma B cells with the 5HT1A antagonist leads to activation of GSK3‐beta and a downregulation of c‐MYC and cyclin D1 mRNA transcripts. Collectively, our data indicate that modulation of serotonin signaling may have potential for treatment of B cell‐derived lymphomas.

  • 2.
    Kolan, Shrikant S
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Immunologi/immunkemi.
    Lidström, Tommy
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Immunologi/immunkemi.
    Mediavilla, Tomás
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Dernstedt, Andy
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Immunologi/immunkemi.
    Degerman, Sofie
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Hultdin, Magnus
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Björk, Karl
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Immunologi/immunkemi.
    Marcellino, Daniel
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Forsell, Mattias N. E.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Immunologi/immunkemi.
    Growth-inhibition of cell lines derived from B cell lymphomas through antagonism of serotonin receptor signaling2019Ingår i: Scientific Reports, E-ISSN 2045-2322, Vol. 9, artikel-id 4276Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A majority of lymphomas are derived from B cells and novel treatments are required to treat refractory disease. Neurotransmitters such as serotonin and dopamine influence activation of B cells and the effects of a selective serotonin 1A receptor (5HT1A) antagonist on growth of a number of B cell-derived lymphoma cell lines were investigated. We confirmed the expression of 5HT1A in human lymphoma tissue and in several well-defined experimental cell lines. We discovered that the pharmacological inhibition of 5HT1A led to the reduced proliferation of B cell-derived lymphoma cell lines together with DNA damage, ROS-independent caspase activation and apoptosis in a large fraction of cells. Residual live cells were found ‘locked’ in a non-proliferative state in which a selective transcriptional and translational shutdown of genes important for cell proliferation and metabolism occurred (e.g., AKT, GSK-3β, cMYC and p53). Strikingly, inhibition of 5HT1A regulated mitochondrial activity through a rapid reduction of mitochondrial membrane potential and reducing dehydrogenase activity. Collectively, our data suggest 5HT1A antagonism as a novel adjuvant to established cancer treatment regimens to further inhibit lymphoma growth.

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  • 3.
    Lidström, Tommy
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Immunosuppressive and metastasis-promoting matrisome proteins in pancreatic cancer: the role of galectin 4 and SERPINB52022Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    In Sweden 1200-1300 people are diagnosed with pancreatic ductal adenocarcinoma (PDAC) every year. Late diagnosis, together with poor treatment response and resistance to checkpoint inhibitor immunotherapy, contributes to the poor prognosis of the disease. 

    PDAC is characterized by abundant deposits of extracellular matrix, which mainly includes structural proteins including collagens, proteoglycans, cell-binding glycoproteins, carbohydrates, and secreted proteins, all constituting the matrisome of the tumor. The matrisome protects cancer cells and affects the outcome. Several highly expressed matrisome proteins are involved in oncogenesis, including the processes of immunosuppression and metastasis formation, therefore contributing to the poor prognosis. In this thesis the pathophysiological role of several matrisome proteins in PDAC tumor progression was studied. Unbiased analysis of matrisome proteins in PDAC tumors revealed increased levels of cancer cell-derived secreted proteins compared to normal healthy control tissue. Subsequently, differentially expressed candidate proteins, with known cellular functions in other disease but hitherto uncharacterized role in PDAC progression, were selected.

    Serine protease inhibitor clade B member 5 (SERPINB5), agrin, and cystatin B (CSTB), were selected for the study described in paper I based on their known roles in the metastasis formation process in other types of cancers. SERPINB5, agrin and CSTB were found to increase metastasis in models of PDAC by affecting epithelial to mesenchymal transition, ECM degradation and extravasation. In PDAC tumors, high levels of extracellular SERPINB5 correlated to reduced overall survival.  

    Galectin 4 (Gal 4) was selected for the study described in paper II based on its known immunosuppressive effects. Gal 4 is highly expressed in PDAC and was found to inhibit T cell infiltration and induce apoptosis in CD8+ T cells by binding to CD3 on the surface of T cells. Gal 4 was associated with better survival in PDAC patients and correlated to higher activation and cytolytic effect of CD8+ T cells.

    The relation between gal 4 and other immunosuppressive proteins was studied in paper III. Analysis of available datasets revealed that gal 4 expression correlates with other cancer cell-derived immunosuppressive proteins of the galectin family, galectin 3 and galectin 9, while negatively correlating with the stroma-derived factors galectin-1 and TGFBI.

    Findings in this thesis show that targeting of matrisome proteins in PDAC can be a promising therapy strategy. Blocking extracellular SERPINB5 could result in reduced metastasis and increased survival. Blocking intracellular gal 4 could increase anti-tumor immunity and synergize with checkpoint inhibition therapy.

    The identified co-expression and coregulation of different immunosuppressive proteins indicate that different tumors can be classified based on their predominant immunosuppressive mechanisms. Following this classification in individual patients, combinations of therapies against different immunosuppressive mechanisms could represent a promising strategy to introduce effective immunotherapies for PDAC patients.  

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  • 4.
    Lidström, Tommy
    et al.
    Umeå universitet, Medicinska fakulteten, Wallenberg centrum för molekylär medicin vid Umeå universitet (WCMM). Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper.
    Cumming, Joshua
    Umeå universitet, Medicinska fakulteten, Wallenberg centrum för molekylär medicin vid Umeå universitet (WCMM). Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper.
    Gaur, Rahul
    Umeå universitet, Medicinska fakulteten, Wallenberg centrum för molekylär medicin vid Umeå universitet (WCMM). Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper.
    Frängsmyr, Lars
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Pateras, Ioannis S.
    2nd Department of Pathology, "Attikon" University Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
    Mickert, Matthias J.
    Lumito AB, Lund, Sweden.
    Franklin, Oskar
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap.
    Forsell, Mattias N. E.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Arnberg, Niklas
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Dongre, Mitesh
    Umeå universitet, Medicinska fakulteten, Wallenberg centrum för molekylär medicin vid Umeå universitet (WCMM). Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper.
    Patthey, Cedric
    Umeå universitet, Medicinska fakulteten, Wallenberg centrum för molekylär medicin vid Umeå universitet (WCMM). Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper.
    Öhlund, Daniel
    Umeå universitet, Medicinska fakulteten, Wallenberg centrum för molekylär medicin vid Umeå universitet (WCMM). Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper.
    Extracellular galectin 4 drives immune evasion and promotes T-cell apoptosis in pancreatic cancer2023Ingår i: Cancer immunology research, ISSN 2326-6066, Vol. 11, nr 1, s. 72-92Artikel i tidskrift (Refereegranskat)
    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. 

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  • 5.
    Lidström, Tommy
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Patthey, Cedric
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Öhlund, Daniel
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Coordination and cooperation of immunosuppressive mechanisms in pancreatic ductal adenocarcinomaManuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    The ability to evade the immune system is crucial for cancer cells to survive. In pancreatic ductal adenocarcinoma (PDAC), various mechanisms contributing to immunosuppression have been described, including the recruitment of suppressive immune cells like M2 macrophages, the expression of cell membrane attached proteins like PDL-1, or secretion of extracellular proteins inducing immune cell apoptosis. PDAC is characterized by a rich stroma, consisting of large quantities of extracellular matrix (ECM) proteins, immune cells, fibroblasts and blood vessels. Cancer cell-derived proteins deposited in the stroma can inhibit immune cell function and thereby contribute to the progression of the disease. Galectin 4 (gal 4) is highly expressed by PDAC cancer cells and is secreted into the stroma and has recently been shown to have the capacity to induce T-cell apoptosis in PDAC tumor. High levels of gal 4 is also associated to poor prognosis and reduced immune activity in PDAC patients. Here we show that sets of immunosuppressive genes form groups based on correlation of expression levels. Gal 4 gene expression correlates with other galectin family proteins, collectively clustering into a distinct immune evasion group. This cluster has negative correlation to other more classical immunosuppressive factors, such as PDL-1, CXCL12, and TGFBI, indicating that a subset of tumors mainly relies on galectins to achieve immune evasion. Conversely, tumors with low expression of gal 4 have high expression of one or more of the classical immunosuppressive factors. These results indicate that different tumors rely on different mechanisms to achieve immune evasion and emphasize the need for personalized treatment strategies when targeting immunosuppression in PDAC.  

  • 6. Tian, Chenxi
    et al.
    Öhlund, Daniel
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi. Umeå universitet, Medicinska fakulteten, Wallenberg centrum för molekylär medicin vid Umeå universitet (WCMM). Cold Spring Harbor Laboratory, Cold Spring Harbor, New York.
    Rickelt, Steffen
    Lidström, Tommy
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi. Umeå universitet, Medicinska fakulteten, Wallenberg centrum för molekylär medicin vid Umeå universitet (WCMM).
    Huang, Ying
    Hao, Liangliang
    Zhao, Renee T.
    Franklin, Oskar
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Kirurgi.
    Bhatia, Sangeeta N.
    Tuveson, David A.
    Hynes, Richard O.
    Cancer cell-derived matrisome proteins promote metastasis in pancreatic ductal adenocarcinoma2020Ingår i: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 80, nr 7, s. 1461-1474Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The prognosis for pancreatic ductal adenocarcinoma (PDAC) remains poor despite decades of effort. The abundant extracellular matrix (ECM) in PDAC comprises a major fraction of the tumor mass and plays various roles in promoting resistance to therapies. However, nonselective depletion of ECM has led to poor patient outcomes. Consistent with that observation, we previously showed that individual matrisome proteins derived from stromal cells correlate with either long or short patient survival. In marked contrast, those derived from cancer cells correlate strongly with poor survival. Here, we studied three cancer cell-derived matrisome proteins that are significantly overrepresented during PDAC progression, AGRN (agrin), SER-PINB5 (serine protease inhibitor B5), and CSTB (cystatin B). Using both overexpression and knockdown experiments, we demonstrate that all three are promoters of PDAC metastasis. Furthermore, these proteins operate at different metastatic steps. AGRN promoted epithelial-to-mesenchymal transition in primary tumors, whereas SERPINB5 and CSTB enhanced late steps in the metastatic cascade by elevating invadopodia formation and in vivo extravasation. All three genes were associated with a poor prognosis in human patients and high levels of SERPINB5, secreted by cancer cells and deposited in the ECM, correlated with poor patient prognosis. This study provides strong evidence that cancer cell-derived matrisome proteins can be causal in promoting tumorigenesis and metastasis and lead to poor patient survival. Therefore, compared with the bulk matrix, mostly made by stromal cells, precise interventions targeting cancer cell-derived matrisome proteins, such as AGRN, SERPINB5, and CSTB, may represent preferred potential therapeutic targets. Significance: This study provides insights into the biological roles of cancer cell-derived matrisome proteins in PDAC and supports the notion that these proteins are protumorigenic and better therapeutic targets.

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