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Yakymovych, I., Yakymovych, M. & Heldin, C.-H. (2018). Intracellular trafficking of transforming growth factor beta receptors. Acta biochimica et biophysica Sinica, 50(1), 3-11
Open this publication in new window or tab >>Intracellular trafficking of transforming growth factor beta receptors
2018 (English)In: Acta biochimica et biophysica Sinica, ISSN 1672-9145, Vol. 50, no 1, p. 3-11Article, review/survey (Refereed) Published
Abstract [en]

Transforming growth factor beta (TGF beta) family members signal via heterotetrameric complexes of type I (T beta RI) and type II (T beta RII) dual specificity kinase receptors. The availability of the receptors on the cell surface is controlled by several mechanisms. Newly synthesized T beta RI and T beta RII are delivered from the Golgi apparatus to the cell surface via separate routes. On the cell surface, TGF beta receptors are distributed between different microdomains of the plasma membrane and can be internalized via clathrin- and caveolae-mediated endocytic mechanisms. Although receptor endocytosis is not essential for TGF beta signaling, localization of the activated receptor complexes on the early endosomes promotes TGF beta-induced Smad activation. Caveolae-mediated endocytosis, which is widely regarded as a mechanism that facilitates the degradation of TGF beta receptors, has been shown to be required for TGF beta signaling via non-Smad pathways. The importance of proper control of TGF beta receptor intracellular trafficking is emphasized by clinical data, as mislocalization of receptors has been described in connection with several human diseases. Thus, control of intracellular trafficking of the TGF beta receptors together with the regulation of their expression, posttranslational modifications and down-regulation, ensure proper regulation of TGF beta signaling.

Place, publisher, year, edition, pages
Oxford University Press, 2018
Keywords
TGF beta receptor, endocytosis, clathrin, lipid rafts, endosome
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-350115 (URN)10.1093/abbs/gmx119 (DOI)000423304200002 ()29186283 (PubMedID)
Available from: 2018-05-07 Created: 2018-05-07 Last updated: 2018-05-07Bibliographically 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
Sundqvist, A., Morikawa, M., Ren, J., Vasilaki, E., Kawasaki, N., Kobayashi, M., . . . ten Dijke, P. (2018). JUNB governs a feed-forward network of TGF beta signaling that aggravates breast cancer invasion. Nucleic Acids Research, 46(3), 1180-1195
Open this publication in new window or tab >>JUNB governs a feed-forward network of TGF beta signaling that aggravates breast cancer invasion
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2018 (English)In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 46, no 3, p. 1180-1195Article in journal (Refereed) Published
Abstract [en]

It is well established that transforming growth factor-beta (TGF beta) switches its function from being a tumor suppressor to a tumor promoter during the course of tumorigenesis, which involves both cell-intrinsic and environment-mediated mechanisms. We are interested in breast cancer cells, in which SMAD mutations are rare and interactions between SMAD and other transcription factors define pro-oncogenic events. Here, we have performed chromatin immunoprecipitation (ChIP)-sequencing analyses which indicate that the genome-wide landscape of SMAD2/3 binding is altered after prolonged TGF beta stimulation. De novo motif analyses of the SMAD2/3 binding regions predict enrichment of binding motifs for activator protein (AP) 1 in addition to SMAD motifs. TGF beta-induced expression of the AP1 component JUNB was required for expression of many late invasion-mediating genes, creating a feed-forward regulatory network. Moreover, we found that several components in the WNT pathway were enriched among the late TGF beta-target genes, including the invasion-inducing WNT7 proteins. Consistently, overexpression of WNT7A or WNT7B enhanced and potentiated TGF beta-induced breast cancer cell invasion, while inhibition of the WNT pathway reduced this process. Our study thereby helps to explain how accumulation of pro-oncogenic stimuli switches and stabilizes TGF beta-induced cellular phenotypes of epithelial cells.

Place, publisher, year, edition, pages
OXFORD UNIV PRESS, 2018
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-349356 (URN)10.1093/nar/gkx1190 (DOI)000425294400020 ()29186616 (PubMedID)
Funder
Swedish Cancer Society, 09 0773, 10 0452, 2016/445Swedish Research Council, 2015-02757
Available from: 2018-05-02 Created: 2018-05-02 Last updated: 2018-05-02Bibliographically approved
Mehic, M. S., de Sa, V. K., Hebestreit, S., Heldin, P. & Heldin, C.-H. S. (2018). The role of deubiquitinating enzyme USP17, hyaluronan synthase 2, and hyaluronan in non-small-cell lung cancer oncogenic transformation. Paper presented at International Conference of the American-Association-for-Cancer-Research (AACR), MAY 04-06, 2017, Sao Paulo, BRAZIL. Clinical Cancer Research, 24(1), 96-96
Open this publication in new window or tab >>The role of deubiquitinating enzyme USP17, hyaluronan synthase 2, and hyaluronan in non-small-cell lung cancer oncogenic transformation
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2018 (English)In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 24, no 1, p. 96-96Article in journal, Meeting abstract (Other academic) Published
Abstract [en]

Introduction: Lung cancer is the result of a multistep accumulation of genetic and/or epigenetic alterations; therefore, a better understanding of the molecular mechanism by which these alterations affect lung cancer pathogenesis would provide new diagnostic procedures and prognostic factors for early detection of recurrence. The remarkable qualitative and quantitative modifications of extracellular matrix components as the deubiquitinating enzyme (USP17), hyaluronan (HA), and hyaluronan synthases 2 (HAS 2) may favor invasion, cellular motility, and proliferation in several cancers including lung.

Results: The silencing of USP17 led to decreased hyaluronan production, whereas the suppression of USP4 increased hyaluronan synthesis. Importantly, high levels of USP17 and HAS2 were detected in a panel of cancer cell lines compared to normal cells, and immunohistochemical stainings revealed higher expression of USP17 and HAS2 in tissues of lung cancer patients compared to normal tissue. Numerous epithelial cells expressed USP17 and HAS2 in dysplasia compared to squamous cell carcinoma (SqCC) (p=0.001). USP17 and HAS2 were prominently expressed in adenocarcinoma (ADC) (p≤0.005). HA immunostaining indexes were increased in ADC and SqCC compared to normal and dysplasia cells (p=0.05). Consistent with the immunohistochemical analyses, low amounts of hyaluronan and USP17 were observed in SqCC by confocal analysis, coincident with less colocalization as determined by confocal microscopy. In contrast, a high expression of hyaluronan (48% of positive index) and high USP17 expression (78% of positive index) in ADC was consistent with a higher degree of colocalization.

Conclusions: HAS2, hyaluronan and USP17 were expressed at higher levels in particular in preneoplastic lesions and ADC, suggesting a role in NSCLC oncogenic transformation, possibly by promoting cellular division by USP17-mediated. Elucidation of the mechanism of how USP17 and HAS2 cooperate in the regulation of the cell cycle might be of therapeutic importance.

National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-347110 (URN)10.1158/1557-3265.TCM17-B64 (DOI)000419180000165 ()
Conference
International Conference of the American-Association-for-Cancer-Research (AACR), MAY 04-06, 2017, Sao Paulo, BRAZIL
Available from: 2018-03-26 Created: 2018-03-26 Last updated: 2018-03-26Bibliographically approved
Kawasaki, N., Isogaya, K., Dan, S., Yamori, T., Takano, H., Yao, R., . . . Koinuma, D. (2018). TUFT1 interacts with RABGAP1 and regulates mTORC1 signaling. CELL DISCOVERY, 4, Article ID 1.
Open this publication in new window or tab >>TUFT1 interacts with RABGAP1 and regulates mTORC1 signaling
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2018 (English)In: CELL DISCOVERY, ISSN 2056-5968, Vol. 4, article id 1Article in journal (Refereed) Published
Abstract [en]

The mammalian target of rapamycin (mTOR) pathway is commonly activated in human cancers. The activity of mTOR complex 1 (mTORC1) signaling is supported by the intracellular positioning of cellular compartments and vesicle trafficking, regulated by Rab GTPases. Here we showed that tuftelin 1 (TUFT1) was involved in the activation of mTORC1 through modulating the Rab GTPase-regulated process. TUFT1 promoted tumor growth and metastasis. Consistently, the expression of TUFT1 correlated with poor prognosis in lung, breast and gastric cancers. Mechanistically, TUFT1 physically interacted with RABGAP1, thereby modulating intracellular lysosomal positioning and vesicular trafficking, and promoted mTORC1 signaling. In addition, expression of TUFT1 predicted sensitivity to perifosine, an alkylphospholipid that alters the composition of lipid rafts. Perifosine treatment altered the positioning and trafficking of cellular compartments to inhibit mTORC1. Our observations indicate that TUFT1 is a key regulator of the mTORC1 pathway and suggest that it is a promising therapeutic target or a biomarker for tumor progression.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2018
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-343387 (URN)10.1038/s41421-017-0001-2 (DOI)000422716800001 ()29423269 (PubMedID)
Funder
Swedish Cancer SocietySwedish Research Council
Available from: 2018-02-28 Created: 2018-02-28 Last updated: 2018-02-28Bibliographically approved
Burmakin, M., van Wieringen, T., Olsson, P. O., Stuhr, L., Åhgren, A., Heldin, C.-H., . . . Hellberg, C. (2017). Imatinib increases oxygen delivery in extracellular matrix-rich but not in matrix-poor experimental carcinoma. Journal of Translational Medicine, 15, Article ID 47.
Open this publication in new window or tab >>Imatinib increases oxygen delivery in extracellular matrix-rich but not in matrix-poor experimental carcinoma
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2017 (English)In: Journal of Translational Medicine, ISSN 1479-5876, E-ISSN 1479-5876, Vol. 15, article id 47Article in journal (Refereed) Published
Abstract [en]

Background: Imatinib causes increased turnover of stromal collagen, reduces collagen fibril diameter, enhances extracellular fluid turnover and lowers interstitial fluid pressure (IFP) in the human colonic carcinoma KAT-4/HT-29 (KAT-4) xenograft model. Methods: We compared the effects of imatinib on oxygen levels, vascular morphology and IFP in three experimental tumor models differing in their content of a collagenous extracellular matrix. Results: Neither the KAT4 and CT-26 colonic carcinoma models, nor B16BB melanoma expressed PDGF beta-receptors in the malignant cells. KAT-4 tumors exhibited a well-developed ECM in contrast to the other two model systems. The collagen content was substantially higher in KAT-4 than in CT-26, while collagen was not detectable in B16BB tumors. The pO(2) was on average 5.4, 13.9 and 19.3 mmHg in KAT-4, CT-26 and B16BB tumors, respectively. Treatment with imatinib resulted in similar pO(2)-levels in all three tumor models but only in KAT-4 tumors did the increase reach statistical significance. It is likely that after imatinib treatment the increase in pO(2) in KAT-4 tumors is caused by increased blood flow due to reduced vascular resistance. This notion is supported by the significant reduction observed in IFP in KAT-4 tumors after imatinib treatment. Vessel area varied between 4.5 and 7% in the three tumor models and was not affected by imatinib treatment. Imatinib had no effect on the fraction of proliferating cells, whereas the fraction of apoptotic cells increased to a similar degree in all three tumor models. Conclusion: Our data suggest that the effects of imatinib on pO(2)-levels depend on a well-developed ECM and provide further support to the suggestion that imatinib acts by causing interstitial stroma cells to produce a less dense ECM, which would in turn allow for an increased blood flow. The potential of imatinib treatment to render solid tumors more accessible to conventional treatments would therefore depend on the degree of tumor desmoplasia.

Place, publisher, year, edition, pages
BioMed Central, 2017
Keywords
Hypoxia, Interstitial fluid pressure, Receptor tyrosine kinase, Tumor stroma
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-320452 (URN)10.1186/s12967-017-1142-7 (DOI)000395566200004 ()28231806 (PubMedID)
Available from: 2017-04-26 Created: 2017-04-26 Last updated: 2017-11-15Bibliographically approved
Gudey, S. K., Sundar, R., Heldin, C.-H., Bergh, A. & Landström, M. (2017). Pro-invasive properties of Snail1 are regulated by sumoylation in response to TGF beta stimulation in cancer. OncoTarget, 8(58), 97703-97726
Open this publication in new window or tab >>Pro-invasive properties of Snail1 are regulated by sumoylation in response to TGF beta stimulation in cancer
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2017 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, no 58, p. 97703-97726Article in journal (Refereed) Published
Abstract [en]

Transforming growth factor beta (TGF beta) is a key regulator of epithelial-tomesenchymal transition (EMT) during embryogenesis and in tumors. The effect of TGF beta, on EMT, is conveyed by induction of the pro-invasive transcription factor Snail1. In this study, we report that TGF beta stimulates Snail1 sumoylation in aggressive prostate, breast and lung cancer cells. Sumoylation of Snail1 lysine residue 234 confers its transcriptional activity, inducing the expression of classical EMT genes, as well as TGF beta receptor I (T beta RI) and the transcriptional repressor Hes1. Mutation of Snail1 lysine residue 234 to arginine (K234R) abolished sumoylation of Snail1, as well as its migratory and invasive properties in human prostate cancer cells. An increased immunohistochemical expression of Snail1, Sumo1, T beta RI, Hes1, and c-Jun was observed in aggressive prostate cancer tissues, consistent with their functional roles in tumorigenesis.

Place, publisher, year, edition, pages
IMPACT JOURNALS LLC, 2017
Keywords
signal transduction, tumor biology, Snail1, sumoylation, prostate cancer
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-345220 (URN)000419392300002 ()29228645 (PubMedID)
Available from: 2018-03-08 Created: 2018-03-08 Last updated: 2018-03-08Bibliographically approved
Bellomo, C., Caja, L., Fabregat, I., Mikulits, W., Kardassis, D., Heldin, C.-H. & Moustakas, A. (2017). Snail mediates crosstalk between TGFβ and LXRα in hepatocellular carcinoma.. Cell Death and Differentiation
Open this publication in new window or tab >>Snail mediates crosstalk between TGFβ and LXRα in hepatocellular carcinoma.
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2017 (English)In: Cell Death and Differentiation, ISSN 1350-9047, E-ISSN 1476-5403Article in journal (Refereed) Epub ahead of print
Abstract [en]

Understanding the complexity of changes in differentiation and cell survival in hepatocellular carcinoma (HCC) is essential for the design of new diagnostic tools and therapeutic modalities. In this context, we have analyzed the crosstalk between transforming growth factor β (TGFβ) and liver X receptor α (LXRα) pathways. TGFβ is known to promote cytostatic and pro-apoptotic responses in HCC, and to facilitate mesenchymal differentiation. We here demonstrate that stimulation of the nuclear LXRα receptor system by physiological and clinically useful agonists controls the HCC response to TGFβ. Specifically, LXRα activation antagonizes the mesenchymal, reactive oxygen species and pro-apoptotic responses to TGFβ and the mesenchymal transcription factor Snail mediates this crosstalk. In contrast, LXRα activation and TGFβ cooperate in enforcing cytostasis in HCC, which preserves their epithelial features. LXRα influences Snail expression transcriptionally, acting on the Snail promoter. These findings propose that clinically used LXR agonists may find further application to the treatment of aggressive, mesenchymal HCCs, whose progression is chronically dependent on autocrine or paracrine TGFβ.

National Category
Medical and Health Sciences Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-339262 (URN)10.1038/s41418-017-0021-3 (DOI)29230000 (PubMedID)
Available from: 2018-01-17 Created: 2018-01-17 Last updated: 2018-04-04Bibliographically approved
Mehić, M., de Sa, V. K., Hebestreit, S., Heldin, C.-H. & Heldin, P. (2017). The deubiquitinating enzymes USP4 and USP17 target hyaluronan synthase 2 and differentially affect its function. Oncogenesis, 6, Article ID e348.
Open this publication in new window or tab >>The deubiquitinating enzymes USP4 and USP17 target hyaluronan synthase 2 and differentially affect its function
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2017 (English)In: Oncogenesis, E-ISSN 2157-9024, Vol. 6, article id e348Article in journal (Refereed) Published
Abstract [en]

The levels of hyaluronan, a ubiquitous glycosaminoglycan prominent in the extracellular matrix, is balanced through the actions of hyaluronan-synthesizing enzymes (HAS1, 2 and 3) and degrading hyaluronidases (Hyal 1, 2, 3 and PH20). Hyaluronan accumulates in rapidly remodeling tissues, such as breast cancer, due to deregulated expression of the HAS2 gene and/or alterations of HAS2 activity. The activity of HAS2 is regulated by post-translational modifications, including ubiquitination. In order to identify deubiquitinating enzymes (DUBs) that are involved in de-ubiquitination of HAS2, a complementary (cDNA) library of 69 Flag-HA-tagged human DUBs cloned into retroviral vectors was screened in human embryonic kidney (HEK) 293T cells for their ability to de-ubiquitinate myc-tagged HAS2. Several DUBs were found to decrease the ubiquitination of 6myc-HAS2, among which, the most effective were USP17 and USP4. USP17 efficiently removed polyubiquitination, whereas USP4 preferentially removed monoubiquitination of 6myc-HAS2. Co-immunoprecipitation studies revealed interactions between HAS2 and USP17, as well as between HAS2 and USP4, in membrane preparations of HEK293T cells. USP17 significantly stabilized 6myc-HAS2 protein levels, whereas USP4 did not. The silencing of USP17 led to decreased hyaluronan production, whereas the suppression of USP4 increased hyaluronan synthesis. Importantly, high levels of USP17 and HAS2 were detected in a panel of cancer cell lines compared to normal cells, and immunohistochemical stainings revealed higher expression of USP17 and HAS2 in tissues of lung cancer patients compared to normal tissue. In conclusion, USP17 and USP4 differently affect HAS2 ubiquitination, and the stability and function of HAS2.

Keywords
cell cycle, ubiquitination, DUBs, growth, hyaluronan, cancer
National Category
Cell and Molecular Biology
Research subject
Biology with specialization in Molecular Biology; Biochemistry
Identifiers
urn:nbn:se:uu:diva-312483 (URN)10.1038/oncsis.2017.45 (DOI)000406047300003 ()28604766 (PubMedID)
Funder
Swedish Cancer Society
Available from: 2017-01-12 Created: 2017-01-10 Last updated: 2018-01-13Bibliographically approved
Christian, J. L. & Heldin, C.-H. (2017). The TGFβ superfamily in Lisbon: navigating through development and disease. Development, 144(24), 4476-4480
Open this publication in new window or tab >>The TGFβ superfamily in Lisbon: navigating through development and disease
2017 (English)In: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 144, no 24, p. 4476-4480Article in journal, Meeting abstract (Other academic) Published
Abstract [en]

The 10th FASEB meeting ‘The TGFβ Superfamily: Signaling in Development and Disease' took place in Lisbon, Portugal, in July 2017. As we review here, the findings presented at the meeting highlighted the important contributions of TGFβ family signaling to normal development, adult homeostasis and disease, and also revealed novel mechanisms by which TGFβ signals are transduced.

Keywords
BMP, Cancer, TGF beta, Signal transduction
National Category
Developmental Biology
Identifiers
urn:nbn:se:uu:diva-347715 (URN)10.1242/dev.159756 (DOI)000418130900002 ()29254990 (PubMedID)
Funder
Swedish Research Council, 2015-02757Swedish Cancer Society, 2016/445
Available from: 2018-04-06 Created: 2018-04-06 Last updated: 2018-04-06Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-9508-896x

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