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Lennartsson, Johan, Professor
Publications (10 of 49) Show all publications
Tsioumpekou, M., Cunha, S. I., Ma, H., Åhgren, A., Cedervall, J., Olsson, A.-K., . . . Lennartsson, J. (2020). Specific targeting of PDGFR beta in the stroma inhibits growth and angiogenesis in tumors with high PDGF-BB expression. Theranostics, 10(3), 1122-1135
Open this publication in new window or tab >>Specific targeting of PDGFR beta in the stroma inhibits growth and angiogenesis in tumors with high PDGF-BB expression
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2020 (English)In: Theranostics, ISSN 1838-7640, E-ISSN 1838-7640, Vol. 10, no 3, p. 1122-1135Article in journal (Refereed) Published
Abstract [en]

PDGF-BB/PDGFR beta signaling plays an important role during vascularization by mediating pericyte recruitment to the vasculature, promoting the integrity and function of vessels. Until now it has not been possible to assess the specific role of PDGFR beta signaling in tumor progression and angiogenesis due to lack of appropriate animal models and molecular tools. Methods: In the present study, we used a transgenic knock-in mouse strain carrying a silent mutation in the PDGFR beta ATP binding site that allows specific targeting of PDGFR beta using the compound 1-NaPP1. To evaluate the impact of selective PDGFR beta inhibition of stromal cells on tumor growth we investigated four tumor cell lines with no or low PDGFR beta expression, i.e. Lewis lung carcinoma (LLC), EO771 breast carcinoma, B16 melanoma and a version of B16 that had been engineered to overexpress PDGF-BB (B16/PDGF-BB). Results: We found that specific impairment of PDGFR beta kinase activity by 1-NaPP1 treatment efficiently suppressed growth in tumors with high expression of PDGF-BB, i.e. LLC and B16/PDGF-BB, while the clinically used PDGFR beta kinase inhibitor imatinib did not suppress tumor growth. Notably, tumors with low levels of PDGF-BB, i.e. EO771 and B16, neither responded to 1-NaPP1 nor to imatinib treatment. Inhibition of PDGFR beta by either drug impaired tumor vascularization and also affected pericyte coverage; however, specific targeting of PDGFR beta by 1-NaPP1 resulted in a more pronounced decrease in vessel function with increased vessel apoptosis in high PDGF-BB expressing tumors, compared to treatment with imatinib. In vitro analysis of PDGFR beta ASKA mouse embryo fibroblasts and the mesenchymal progenitor cell line 10T1/2 revealed that PDGF-BB induced NG2 expression, consistent with the in vivo data. Conclusion: Specific targeting of PDGFR beta signaling significantly inhibits tumor progression and angiogenesis depending on PDGF-BB expression. Our data suggest that targeting PDGFR beta in the tumor stroma could have therapeutic value in patients with high tumor PDGF-BB expression.

Place, publisher, year, edition, pages
IVYSPRING INT PUBL, 2020
Keywords
Low molecular weight inhibitor, PDGFR beta, pericytes, tumor growth, angiogenesis
National Category
Cell and Molecular Biology Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-402371 (URN)10.7150/thno.37851 (DOI)000503870400011 ()31938055 (PubMedID)
Funder
Swedish Cancer Society, 2018/425Swedish Cancer Society, 2015/445Lars Hierta Memorial FoundationStiftelsen Längmanska kulturfonden
Available from: 2020-02-03 Created: 2020-02-03 Last updated: 2020-02-03Bibliographically approved
Zarei, O., Sarri, N., Dastmalchi, S., Zokai, F., Papadopoulos, N., Lennartsson, J., . . . Hamzeh-Mivehroud, M. (2020). Structure-based discovery of novel small molecule inhibitors of platelet-derived growth factor-B. Bioorganic chemistry (Print), 94, Article ID 103374.
Open this publication in new window or tab >>Structure-based discovery of novel small molecule inhibitors of platelet-derived growth factor-B
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2020 (English)In: Bioorganic chemistry (Print), ISSN 0045-2068, Vol. 94, article id 103374Article in journal (Refereed) Published
Abstract [en]

Platelet-derived growth factor (PDGF) is a family of growth factors with mitogenic and chemotactic activity. However, uncontrolled and overactivated PDGF signaling has been implicated in a variety of diseases, such as cancers and atherosclerosis. In this context, inhibition of PDGF-PDGFR signaling is of paramount importance in progression of such diseases. The purpose of the current study was to identify novel PDGF-B inhibitors using virtual screening methods. To this end, a combination of molecular modeling techniques such as molecular docking and dynamics simulation, as well as drug likeness filtering criteria, was applied to select anti-PDGF peptidomimetic candidates based on crystallography solved structure of an anti-PDGF-B monoclonal antibody named, MOR8457. In vitro biological assays of the selected compounds revealed two of them being active at micromolar IC50, concentrations. The presented work can provide a framework for systematic peptidomimetic identification for anti-PDGF-B agents from large chemical libraries.

Keywords
Virtual screening, Platelet-derived growth factor-B, Molecular docking, Molecular dynamics simulation, Anti-PDGF-B agents, MOR8457 antibody
National Category
Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-403397 (URN)10.1016/j.bioorg.2019.103374 (DOI)000505596300030 ()31699389 (PubMedID)
Funder
Swedish Cancer Society, 2016/445Swedish Cancer Society, 2018/425
Note

Omid Zarei and Niki Sarri contributed equally to this work

Available from: 2020-01-29 Created: 2020-01-29 Last updated: 2020-01-29Bibliographically approved
Yin, R., Eger, G., Sarri, N., Rorsman, C., Heldin, C.-H. & Lennartsson, J. (2019). Dual specificity phosphatase (DUSP)-4 is induced by platelet-derived growth factor -BB in an Erk1/2-, STAT3- and p53-dependent manner. Biochemical and Biophysical Research Communications - BBRC, 519(3), 469-474
Open this publication in new window or tab >>Dual specificity phosphatase (DUSP)-4 is induced by platelet-derived growth factor -BB in an Erk1/2-, STAT3- and p53-dependent manner
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2019 (English)In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 519, no 3, p. 469-474Article in journal (Refereed) Published
Abstract [en]

Dual specificity phosphatase (DUSP) 4 has been described as a negative regulator of MAP kinase signaling, in particular for the ERK1/2 and JNK pathways. We found that DUSP4 expression was upregulated in response to prolonged platelet-derived growth factor (PDGF)-BB stimulation. The PDGF-BB-induced DUSP4 expression was dependent on ERK1/2, STAT3 and p53. We found that inhibition of ERK1/2 effectively reduced DUSP4 mRNA levels, whereas STAT3 was necessary for maintaining p53 expression. p53 has binding sites in the DUSP4 promoter and was found to promote DUSP4 expression.

Keywords
DUSP4, Erk1/2, Multifactor regulation, PDGF, STAT3, p53
National Category
Cell Biology
Identifiers
urn:nbn:se:uu:diva-400210 (URN)10.1016/j.bbrc.2019.09.014 (DOI)000506407800004 ()31526568 (PubMedID)
Funder
Swedish Cancer Society, 2018/425Swedish Cancer Society, 2016/445
Note

De 2 första författarna delar förstaförfattarskapet

Available from: 2019-12-19 Created: 2019-12-19 Last updated: 2020-03-24Bibliographically approved
Heldin, J., Rubin Sander, M., Leino, M., Thomsson, S., Lennartsson, J. & Söderberg, O. (2019). Dynamin inhibitors impair platelet-derived growth factor beta-receptor dimerization and signaling. Experimental Cell Research, 380(1), 69-79
Open this publication in new window or tab >>Dynamin inhibitors impair platelet-derived growth factor beta-receptor dimerization and signaling
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2019 (English)In: Experimental Cell Research, ISSN 0014-4827, E-ISSN 1090-2422, Vol. 380, no 1, p. 69-79Article in journal (Refereed) Published
Abstract [en]

The role of plasma membrane composition and dynamics in the activation process of receptor tyrosine kinases (RTKs) is still poorly understood. In this study we have investigated how signaling via the RTK, platelet-derived growth factor beta-receptor (PDGFR-beta) is affected by Dynasore or Dyngo-4a, which are commonly used dynamin inhibitors. PDGFR-beta preferentially internalizes via clathrin-coated pits and in this pathway, Dynamin II has a major role in the formation and release of vesicles from the plasma membrane by performing the membrane scission. We have found that dynamin inhibitors impedes the activation of PDGFR-beta by impairing ligand-induced dimerization of the receptor monomers, which leads to a subsequent lack of phosphorylation and activation both of receptors and downstream effectors, such as ERK1/2 and AKT. In contrast, dynamin inhibitors did not affect epidermal growth factor receptor (EGFR) dimerization and phosphorylation. Our findings suggest that there is a link between plasma membrane dynamics and PDGFR-beta activation, and that this link is not shared with the epidermal growth factor receptor.

Place, publisher, year, edition, pages
ELSEVIER INC, 2019
Keywords
RTK signaling, EGFR, PDGFR-beta, Dynasore, Dyngo, Dimerization
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-384986 (URN)10.1016/j.yexcr.2019.04.004 (DOI)000468124700008 ()30970237 (PubMedID)
Funder
Swedish Foundation for Strategic Research Swedish Research CouncilSwedish Cancer Society, CAN 2018/425
Available from: 2019-06-14 Created: 2019-06-14 Last updated: 2019-06-14Bibliographically approved
Heldin, C.-H., Lennartsson, J. & Westermark, B. (2018). Involvement of platelet-derived growth factor ligands and receptors in tumorigenesis. Journal of Internal Medicine, 283(1), 16-44
Open this publication in new window or tab >>Involvement of platelet-derived growth factor ligands and receptors in tumorigenesis
2018 (English)In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 283, no 1, p. 16-44Article, review/survey (Refereed) Published
Abstract [en]

Platelet-derived growth factor (PDGF) isoforms and their receptors have important roles during embryogenesis, particularly in the development of various mesenchymal cell types in different organs. In the adult, PDGF stimulates wound healing and regulates tissue homeostasis. However, overactivity of PDGF signalling is associated with malignancies and other diseases characterized by excessive cell proliferation, such as fibrotic conditions and atherosclerosis. In certain tumours, genetic or epigenetic alterations of the genes for PDGF ligands and receptors drive tumour cell proliferation and survival. Examples include the rare skin tumour dermatofibrosarcoma protuberance, which is driven by autocrine PDGF stimulation due to translocation of a PDGF gene, and certain gastrointestinal stromal tumours and leukaemias, which are driven by constitute activation of PDGF receptors due to point mutations and formation of fusion proteins ofthe receptors, respectively. Moreover, PDGF stimulates cells in tumour stroma and promotes angiogenesis as well as the development of cancer-associated fibroblasts, both of which promote tumour progression. Inhibitors of PDGF signalling may thus be of clinical usefulness in the treatment of certain tumours.

Keywords
inhibitor, kinase, malignancy, receptor, signal transduction, PDGF
National Category
Cell and Molecular Biology Cell Biology
Identifiers
urn:nbn:se:uu:diva-347709 (URN)10.1111/joim.12690 (DOI)000418411100002 ()28940884 (PubMedID)
Funder
Swedish Cancer Society, 2016/445; 2015/226; 2014/468Swedish Research Council, 2015-02757
Available from: 2018-04-06 Created: 2018-04-06 Last updated: 2018-04-06Bibliographically approved
Papadopoulos, N., Lennartsson, J. & Heldin, C.-H. (2018). PDGFR beta translocates to the nucleus and regulates chromatin remodeling via TATA element-modifying factor 1. Journal of Cell Biology, 217(5), 1701-1717
Open this publication in new window or tab >>PDGFR beta translocates to the nucleus and regulates chromatin remodeling via TATA element-modifying factor 1
2018 (English)In: Journal of Cell Biology, ISSN 0021-9525, E-ISSN 1540-8140, Vol. 217, no 5, p. 1701-1717Article in journal (Refereed) Published
Abstract [en]

Translocation of full-length or fragments of receptors to the nucleus has been reported for several tyrosine kinase receptors. In this paper, we show that a fraction of full-length cell surface platelet-derived growth factor (PDGF) receptor beta (PDG FR beta) accumulates in the nucleus at the chromatin and the nuclear matrix after ligand stimulation. Nuclear translocation of PDG FR beta was dependent on PDGF-BB-induced receptor dimerization, clathrin-mediated endocytosis, beta-importin, and intact Golgi, occurring in both normal and cancer cells. In the nucleus, PDG FR beta formed ligand-inducible complexes with the tyrosine kinase Fer and its substrate, TATA element-modifying factor 1 (TMF-1). PDGF-BB stimulation decreased TMF-1 binding to the transcriptional regulator Brahma-related gene 1 (Brg-1) and released Brg-1 from the SWI-SNF chromatin remodeling complex. Moreover, knockdown of TMF-1 by small interfering RNA decreased nuclear translocation of PDG FR beta and caused significant up-regulation of the Brg-1/p53-regulated cell cycle inhibitor CDKN1A (encoding p21) without affecting PDG FR beta-inducible immediate-early genes. In conclusion, nuclear interactions of PDG FR beta control proliferation by chromatin remodeling and regulation of p21 levels.

Place, publisher, year, edition, pages
ROCKEFELLER UNIV PRESS, 2018
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-356403 (URN)10.1083/jcb.201706118 (DOI)000431616300016 ()29545370 (PubMedID)
Funder
Swedish Research Council, 2015-02757Swedish Cancer Society, 2016/445Swedish Cancer Society, 140332
Available from: 2018-07-25 Created: 2018-07-25 Last updated: 2018-07-25Bibliographically approved
Papadopoulos, N. & Lennartsson, J. (2018). The PDGF/PDGFR pathway as a drug target. Molecular Aspects of Medicine, 62, 75-88
Open this publication in new window or tab >>The PDGF/PDGFR pathway as a drug target
2018 (English)In: Molecular Aspects of Medicine, ISSN 0098-2997, E-ISSN 1872-9452, Vol. 62, p. 75-88Article, review/survey (Refereed) Published
Abstract [en]

Platelet-derived growth factors (PDGF) promotes cell proliferation, survival and migration, primarily of cells of mesenchymal origin. Dysfunction of PDGF signaling has been observed in a wide array of pathological conditions, such as cancer, fibrosis, neurological conditions and atherosclerosis. Reported abnormalities of the PDGF pathway include overexpression or amplification of PDGF receptors (PDGFRs), gain of function point mutations or activating chromosomal translocations. Current development of therapeutic drugs often aims at producing compounds that specifically target interaction between PDGFs and their receptors by specific DNA aptamers and ligand traps, or downregulate PDGFRs with blocking antibodies, or inhibit tyrosine kinase activity of PDGFRs with small molecules. In this review, we discuss some of the approaches taken to interfere with PDGF signaling, review a panel of existing therapeutic drugs, and consider clinically successful cases and remaining challenges.

Keywords
PDGF pathway, PDGFR, Therapeutics, Drug targeting
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-365117 (URN)10.1016/j.mam.2017.11.007 (DOI)000435085900007 ()29137923 (PubMedID)
Available from: 2018-11-12 Created: 2018-11-12 Last updated: 2018-11-12Bibliographically approved
Reyhani, V., Tsioumpekou, M., van Wieringen, T., Rask, L., Lennartsson, J. & Rubin, K. (2017). PDGF-BB enhances collagen gel contraction through a PI3K-PLCγ-PKC-cofilin pathway. Scientific Reports, 7(1), Article ID 8924.
Open this publication in new window or tab >>PDGF-BB enhances collagen gel contraction through a PI3K-PLCγ-PKC-cofilin pathway
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2017 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, no 1, article id 8924Article in journal (Refereed) Published
Abstract [en]

Cell-mediated contraction of collagenous matrices is modulated by various growth factors and cytokines, such as platelet-derived growth factor-BB (PDGF-BB). Here we used a genetic cell model to delineate defined signaling pathways that enhance collagen gel contraction downstream of ligand-stimulated platelet-derived growth factor receptor-β (PDGF-Rβ). Our data show that PDGF BB-enhanced activations of phosphatidylinositol 3'-kinase (PI3K) and phospholipase Cγ (PLCγ) were necessary for PDGF-enhanced collagen gel contraction. Importantly, other defined signaling pathways down-stream of PDGF-Rβ were, however, dispensable. The decisive roles for PI3K and PLCγ were corroborated by experiments using selective inhibitors. Furthermore, we show that de-phosphorylation and thereby activation of cofilin that is important for the turnover of actin filaments, is depended on PI3K and PLCγ down-stream of PDGF-Rβ. Moreover, inhibition of protein kinase C (PKC) by GÖ6976 and bisindolylmaleimide-II abolished cofilin de-phosphorylation, as well as PDGF-enhanced contraction. In contrast, activation of the PKC protein family by 4β-phorbol 12-myristate 13-acetate (PMA) did not accelerate collagen gel contraction although it induced long-term cofilin de-phosphorylation, showing the need of a dynamic control of cofilin de-phosphorylation for PDGF-enhanced collagen gel contraction. Taken together, our data point to the involvement of a PI3K/PLCγ-PKC-cofilin pathway in both PDGF-enhanced cofilin de-phosphorylation and PDGF-enhanced collagen gel contraction.

National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:uu:diva-331647 (URN)10.1038/s41598-017-08411-1 (DOI)000408107000058 ()28827622 (PubMedID)
Funder
Swedish Cancer SocietySwedish Research Council
Available from: 2017-10-16 Created: 2017-10-16 Last updated: 2018-09-07Bibliographically approved
Rorsman, C., Tsioumpekou, M., Heldin, C.-H. & Lennartsson, J. (2016). The Ubiquitin Ligases c-Cbl and Cbl-b Negatively Regulate Platelet-derived Growth Factor (PDGF) BB-induced Chemotaxis by Affecting PDGF Receptor beta (PDGFR beta) Internalization and Signaling. Journal of Biological Chemistry, 291(22), 11608-11618
Open this publication in new window or tab >>The Ubiquitin Ligases c-Cbl and Cbl-b Negatively Regulate Platelet-derived Growth Factor (PDGF) BB-induced Chemotaxis by Affecting PDGF Receptor beta (PDGFR beta) Internalization and Signaling
2016 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 291, no 22, p. 11608-11618Article in journal (Refereed) Published
Abstract [en]

Protein ubiquitination controls protein stability and subcellular localization of tyrosine kinase receptors, hence affecting signaling both quantitatively and qualitatively. In this report, we demonstrate that, after ligand stimulation, the PDGF beta receptor (PDGFR beta) becomes ubiquitinated in a manner requiring both the c-Cbl and Cbl-b ubiquitin ligases. Simultaneous depletion of c-Cbl and Cbl-b resulted in reduced ligand-induced PDGFR beta clearance from the cell surface because of reduced endocytosis of the receptor. Cbl-b formed a complex with c-Cbl, as well as with the PDGFR beta, in response to PDGF-BB stimulation. We were unable to find a direct interaction between the receptor and c-Cbl, raising the possibility that Cbl-b is necessary for c-Cbl to interact with PDGFR beta. Phosphorylated Tyr-1021 in PDGFR beta was the primary interaction site for Cbl-b, with some contribution from Tyr-1009. Depletion of c-Cbl and Cbl-b led to an increased ligand-induced tyrosine phosphorylation of the receptor. Several tyrosine residues with elevated phosphorylation (i.e. Tyr-579, Tyr-581, Tyr-1009, and Tyr-1021) have previously been shown to interact with Src kinases and PLC gamma. Indeed, in cells depleted of c-Cbl and Cbl-b, both Src and PLC gamma phosphorylation were enhanced, whereas activation of other pathways, such as Erk1/2 MAP kinase and Akt, were not affected. In addition, Stat3 phosphorylation, which has been connected to Src activity, was also elevated in cells lacking c-Cbl and Cbl-b. Functionally, we found that cells depleted of c-Cbl and Cbl-b were more prone to migrate toward PDGF-BB, whereas no reproducible effect on cell proliferation could be observed. In conclusion, internalization as well as signaling via PDGFR beta are controlled by ubiquitination.

National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:uu:diva-299504 (URN)10.1074/jbc.M115.705814 (DOI)000377264800013 ()27048651 (PubMedID)
Funder
Swedish Cancer Society
Available from: 2016-07-22 Created: 2016-07-22 Last updated: 2019-02-03Bibliographically approved
Sooman, L., Freyhult, E., Jaiswal, A., Navani, S., Edqvist, P.-H., Pontén, F., . . . Ekman, S. (2015). FGF2 as a potential prognostic biomarker for proneural glioma patients. Acta Oncologica, 54(3), 385-394
Open this publication in new window or tab >>FGF2 as a potential prognostic biomarker for proneural glioma patients
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2015 (English)In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 54, no 3, p. 385-394Article in journal (Refereed) Published
Abstract [en]

Background. The survival of high-grade glioma patients is poor and the treatment of these patients can cause severe side effects. This fosters the necessity to identify prognostic biomarkers, in order to optimize treatment and diminish unnecessary suffering of patients. The aim of this study was to identify prognostic biomarkers for high-grade glioma patients.

Methods. Eleven proteins were selected for analysis due to their suggested importance for survival of patients with other types of cancers and due to a high variation in protein levels between glioma patients (according to the Human Protein Atlas, www.proteinatlas.org). Protein expression patterns of these 11 proteins were analyzed by immunohistochemistry in tumor samples from 97 high-grade glioma patients. The prognostic values of the proteins were analyzed with univariate and multivariate Cox regression analyses for the high-grade glioma patients, including subgroup analyses of histological subtypes and immunohistochemically defined molecular subtypes.

Results. The proteins with the most significant (univariate and multivariate p < 0.05) correlations were analyzed further with cross-validated Kaplan-Meier analyses for the possibility of predicting survival based on the protein expression pattern of the corresponding candidate. Random Forest classification with variable subset selection was used to analyze if a protein signature consisting of any combination of the 11 proteins could predict survival for the high-grade glioma patients and the subgroup with glioblastoma patients. The proteins which correlated most significantly (univariate and multivariate p < 0.05) to survival in the Cox regression analyses were Myc for all high-grade gliomas and FGF2, CA9 and CD44 for the subgroup of proneural gliomas, with FGF2 having a strong negative predictive value for survival. No prognostic signature of the proteins could be found.

Conclusion. FGF2 is a potential prognostic biomarker for proneural glioma patients, and warrants further investigation.

Keywords
Prognostic biomarkers, tissue microarray, immunohistochemistry, FGF2, CA9, CD44
National Category
Cell and Molecular Biology Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-214802 (URN)10.3109/0284186X.2014.951492 (DOI)000350646400012 ()25263081 (PubMedID)
Available from: 2014-01-09 Created: 2014-01-09 Last updated: 2018-01-11Bibliographically approved
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