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Fryknäs, Mårten
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Publications (10 of 57) Show all publications
Jiang, Y., Marinescu, V. D., Xie, Y., Jarvius, M., Maturi, N. P., Haglund, C., . . . Uhrbom, L. (2017). Glioblastoma Cell Malignancy and Drug Sensitivity Are Affected by the Cell of Origin. Cell reports, 18(4), 977-990
Open this publication in new window or tab >>Glioblastoma Cell Malignancy and Drug Sensitivity Are Affected by the Cell of Origin
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2017 (English)In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 18, no 4, p. 977-990Article in journal (Refereed) Published
Abstract [en]

The identity of the glioblastoma (GBM) cell of origin and its contributions to disease progression and treatment response remain largely unknown. We have analyzed how the phenotypic state of the initially transformed cell affects mouse GBM development and essential GBM cell (GC) properties. We find that GBM induced in neural stem-cell-like glial fibrillary acidic protein (GFAP)-expressing cells in the subventricular zone of adult mice shows accelerated tumor development and produces more malignant GCs (mGC1GFAP) that are less resistant to cancer drugs, compared with those originating from more differentiated nestin- (mGC2NES) or 2,'3'-cyclic nucleotide 3'-phosphodiesterase (mGC3CNP)-expressing cells. Transcriptome analysis of mouse GCs identified a 196 mouse cell origin (MCO) gene signature that was used to partition 61 patient-derived GC lines. Human GC lines that clustered with the mGC1GFAP cells were also significantly more self-renewing, tumorigenic, and sensitive to cancer drugs compared with those that clustered with mouse GCs of more differentiated origin.

Keyword
cancer stem cell, cell of origin, central nervous system, drug response, glioblastoma, glioma, mouse model, neural stem cell, oligodendrocyte precursor cell, self-renewal
National Category
Clinical Laboratory Medicine
Research subject
Pathology
Identifiers
urn:nbn:se:uu:diva-319084 (URN)10.1016/j.celrep.2017.01.003 (DOI)000396474300013 ()28122246 (PubMedID)
Funder
Swedish Cancer Society, 110363 140385 150628Swedish Research Council, 90283201 C0259101 B0310101 E0331401Swedish Childhood Cancer Foundation, PROJ11/057 PR2014-0143Science for Life Laboratory - a national resource center for high-throughput molecular bioscience
Available from: 2017-03-31 Created: 2017-03-31 Last updated: 2017-11-29Bibliographically approved
Karlsson, H., Fryknäs, M., Strese, S., Gullbo, J., Westman, G., Bremberg, U., . . . Nygren, P. (2017). Mechanistic characterization of a copper containing thiosemicarbazone with potent antitumor activity. OncoTarget, 8(18), 30217-30234
Open this publication in new window or tab >>Mechanistic characterization of a copper containing thiosemicarbazone with potent antitumor activity
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2017 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, no 18, p. 30217-30234Article in journal (Refereed) Published
Abstract [en]

Background: The thiosemicarbazone CD 02750 (VLX50) was recently reported as a hit compound in a phenotype-based drug screen in primary cultures of patient tumor cells. We synthesized a copper complex of VLX50, denoted VLX60, and characterized its antitumor and mechanistic properties.

Materials and Methods: The cytotoxic effects and mechanistic properties of VLX60 were investigated in monolayer cultures of multiple human cell lines, in tumor cells from patients, in a 3-D spheroid cell culture system and in vivo and were compared with those of VLX50.

Results: VLX60 showed >= 3-fold higher cytotoxic activity than VLX50 in 2-D cultures and, in contrast to VLX50, retained its activity in the presence of additional iron. VLX60 was effective against non-proliferative spheroids and against tumor xenografts in vivo in a murine model. In contrast to VLX50, gene expression analysis demonstrated that genes associated with oxidative stress were considerably enriched in cells exposed to VLX60 as was induction of reactive oxygen. VLX60 compromised the ubiquitin-proteasome system and was more active in BRAF mutated versus BRAF wild-type colon cancer cells.

Conclusions: The cytotoxic effects of the copper thiosemicarbazone VLX60 differ from those of VLX50 and shows interesting features as a potential antitumor drug, notably against BRAF mutated colorectal cancer.

Place, publisher, year, edition, pages
IMPACT JOURNALS LLC, 2017
Keyword
cancer drug, thiosemicarbazone, spheroid, VLX60, BRAF
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-323035 (URN)10.18632/oncotarget.16324 (DOI)000400456200055 ()28415818 (PubMedID)
Funder
Swedish Cancer SocietySwedish Foundation for Strategic Research
Available from: 2017-06-01 Created: 2017-06-01 Last updated: 2017-11-29Bibliographically approved
Sreedharan, S., Maturi, N. P., Xie, Y., Sundström, A., Jarvius, M., Libard, S., . . . Uhrbom, L. (2017). Mouse models of pediatric supratentorial high-grade glioma reveal how cell-of-origin influences tumor development and phenotype. Cancer Research (3), 802-812
Open this publication in new window or tab >>Mouse models of pediatric supratentorial high-grade glioma reveal how cell-of-origin influences tumor development and phenotype
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2017 (English)In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, no 3, p. 802-812Article in journal (Refereed) Published
Abstract [en]

High-grade glioma (HGG) is a group of primary malignant brain tumors with dismal prognosis. Whereas adult HGG has been studied extensively, childhood HGG, a relatively rare disease, is less well-characterized. Here, we present two novel platelet-derived growth factor (PDGF)-driven mouse models of pediatric supratentorial HGG. Tumors developed from two different cells of origin reminiscent of neural stem cells (NSC) or oligodendrocyte precursor cells (OPC). Cross-species transcriptomics showed that both models are closely related to human pediatric HGG as compared with adult HGG. Furthermore, an NSC-like cell-of-origin enhanced tumor incidence, malignancy, and the ability of mouse glioma cells (GC) to be cultured under stem cell conditions as compared with an OPC-like cell. Functional analyses of cultured GC from these tumors showed that cells of NSC-like origin were more tumorigenic, had a higher rate of self-renewal and proliferation, and were more sensitive to a panel of cancer drugs compared with GC of a more differentiated origin. These two mouse models relevant to human pediatric supratentorial HGG propose an important role of the cell-of-origin for clinicopathologic features of this disease.

Keyword
pediatric high-grade glioma, glioblastoma, mouse model, cell of origin, glioma stem cell
National Category
Cell and Molecular Biology
Research subject
Biomedical Laboratory Science
Identifiers
urn:nbn:se:uu:diva-310215 (URN)10.1158/0008-5472.CAN-16-2482 (DOI)000393194400020 ()
Funder
Swedish Cancer SocietySwedish Childhood Cancer FoundationSwedish Research CouncilSwedish Society for Medical Research (SSMF)
Available from: 2016-12-13 Created: 2016-12-13 Last updated: 2018-03-28Bibliographically approved
Nazir, M., Senkowski, W., Nyberg, F., Blom, K., Edqvist, P.-H. D., Jarvius, M., . . . Fryknäs, M. (2017). Targeting tumor cells based on Phosphodiesterase 3A expression. Experimental Cell Research, 361(2), 308-315
Open this publication in new window or tab >>Targeting tumor cells based on Phosphodiesterase 3A expression
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2017 (English)In: Experimental Cell Research, ISSN 0014-4827, E-ISSN 1090-2422, Vol. 361, no 2, p. 308-315Article in journal (Refereed) Published
Abstract [en]

We and others have previously reported a correlation between high phosphodiesterase 3 A (PDE3A) expression and selective sensitivity to phosphodiesterase (PDE) inhibitors. This indicates that PDE3A could serve both as a drug target and a biomarker of sensitivity to PDE3 inhibition. In this report, we explored publicly available mRNA gene expression data to identify cell lines with different PDE3A expression. Cell lines with high PDE3A expression showed marked in vitro sensitivity to PDE inhibitors zardaverine and quazinone, when compared with those having low PDE3A expression. Immunofluorescence and immunohistochemical stainings were in agreement with PDE3A mRNA expression, providing suitable alternatives for biomarker analysis of clinical tissue specimens. Moreover, we here demonstrate that tumor cells from patients with ovarian carcinoma show great variability in PDE3A protein expression and that level of PDE3A expression is correlated with sensitivity to PDE inhibition. Finally, we demonstrate that PDE3A is highly expressed in subsets of patient tumor cell samples from different solid cancer diagnoses and expressed at exceptional levels in gastrointestinal stromal tumor (GIST) specimens. Importantly, vulnerability to PDE3 inhibitors has recently been associated with co-expression of PDE3A and Schlafen family member 12 (SLFN12). We here demonstrate that high expression of PDE3A in clinical specimens, at least on the mRNA level, seems to be frequently associated with high SLFIV12 expression. In conclusion, PDE3A seems to be both a promising biomarker and drug target for individualized drug treatment of various cancers.

Keyword
Repositioning, Cancer, Therapy, PDE3A, Biomarker
National Category
Cancer and Oncology Cell Biology
Identifiers
urn:nbn:se:uu:diva-339786 (URN)10.1016/j.yexcr.2017.10.032 (DOI)000417774300013 ()29107068 (PubMedID)
Funder
Swedish Cancer Society, 2016/335Swedish Research Council, 2016-01112
Available from: 2018-02-16 Created: 2018-02-16 Last updated: 2018-04-04Bibliographically approved
Blom, K., Senkowski, W., Jarvius, M., Berglund, M., Rubin, J., Lenhammar, L., . . . Larsson, R. (2017). The anticancer effect of mebendazole may be due to M1 monocyte/macrophage activation via ERK1/2 and TLR8-dependent inflammasome activation. Immunopharmacology and immunotoxicology, 39(4), 199-210
Open this publication in new window or tab >>The anticancer effect of mebendazole may be due to M1 monocyte/macrophage activation via ERK1/2 and TLR8-dependent inflammasome activation
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2017 (English)In: Immunopharmacology and immunotoxicology, ISSN 0892-3973, E-ISSN 1532-2513, Vol. 39, no 4, p. 199-210Article in journal (Refereed) Published
Abstract [en]

Mebendazole (MBZ), a drug commonly used for helminitic infections, has recently gained substantial attention as a repositioning candidate for cancer treatment. However, the mechanism of action behind its anticancer activity remains unclear. To address this problem, we took advantage of the curated MBZ-induced gene expression signatures in the LINCS Connectivity Map (CMap) database. The analysis revealed strong negative correlation with MEK/ERK1/2 inhibitors. Moreover, several of the most upregulated genes in response to MBZ exposure were related to monocyte/macrophage activation. The MBZ-induced gene expression signature in the promyeloblastic HL-60 cell line was strongly enriched in genes involved in monocyte/macrophage pro-inflammatory (M1) activation. This was subsequently validated using MBZ-treated THP-1 monocytoid cells that demonstrated gene expression, surface markers and cytokine release characteristic of the M1 phenotype. At high concentrations MBZ substantially induced the release of IL-1 beta and this was further potentiated by lipopolysaccharide (LPS). At low MBZ concentrations, cotreatment with LPS was required for MBZ-stimulated IL-1 beta secretion to occur. Furthermore, we show that the activation of protein kinase C, ERK1/2 and NF-kappaB were required for MBZ-induced IL-1 release. MBZ-induced IL-1 release was found to be dependent on NLRP3 inflammasome activation and to involve TLR8 stimulation. Finally, MBZ induced tumor-suppressive effects in a coculture model with differentiated THP-1 macrophages and HT29 colon cancer cells. In summary, we report that MBZ induced a pro-inflammatory (M1) phenotype of monocytoid cells, which may, at least partly, explain MBZ's anticancer activity observed in animal tumor models and in the clinic.

Keyword
Repositioning, cancer therapy, monocytes, macrophages, mebendazole
National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:uu:diva-329149 (URN)10.1080/08923973.2017.1320671 (DOI)000403934300005 ()28472897 (PubMedID)
Funder
Swedish Cancer Society
Available from: 2017-09-15 Created: 2017-09-15 Last updated: 2018-01-13Bibliographically approved
Eriksson, A., Chantzi, E., Fryknäs, M., Gullbo, J., Nygren, P., Gustafsson, M. G., . . . Larsson, R. (2017). Towards repositioning of quinacrine for treatment of acute myeloid leukemia - Promising synergies and in vivo effects.. Leukemia research: a Forum for Studies on Leukemia and Normal Hemopoiesis, 63, 41-46
Open this publication in new window or tab >>Towards repositioning of quinacrine for treatment of acute myeloid leukemia - Promising synergies and in vivo effects.
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2017 (English)In: Leukemia research: a Forum for Studies on Leukemia and Normal Hemopoiesis, ISSN 0145-2126, E-ISSN 1873-5835, Vol. 63, p. 41-46Article in journal (Refereed) Published
Abstract [en]

We previously reported that the anti-malarial drug quinacrine has potential to be repositioned for treatment of acute myeloid leukemia (AML). As a next step towards clinical use, we assessed the efficacy of quinacrine in an AML-PS mouse model and investigated possible synergistic effects when combining quinacrine with nine other antileukemic compounds in two AML cell lines. Furthermore, we explored the in vivo activity of quinacrine in combination with the widely used AML agent cytarabine. The in vivo use of quinacrine (100mg/kg three times per week for two consecutive weeks) significantly suppressed circulating blast cells at days 30/31 and increased the median survival time (MST). The in vitro drug combination analysis yielded promising synergistic interactions when combining quinacrine with cytarabine, azacitidine and geldanamycin. Finally, combining quinacrine with cytarabine in vivo showed a significant decrease in circulating leukemic blast cells and increased MST compared to the effect of either drug used alone, thus supporting the findings from the in vitro combination experiments. Taken together, the repositioning potential of quinacrine for treatment of AML is reinforced by demonstrating significant in vivo activity and promising synergies when quinacrine is combined with different agents, including cytarabine, the hypomethylating agent azacitidine and HSP-90 inhibitor geldanamycin.

Keyword
Acute myeloid leukemia, Drug combinations, Quinacrine, Repositioning
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-342993 (URN)10.1016/j.leukres.2017.10.012 (DOI)000416744700007 ()29100024 (PubMedID)
Available from: 2018-02-24 Created: 2018-02-24 Last updated: 2018-03-01Bibliographically approved
Segerman, A., Niklasson, M., Haglund, C., Bergström, T., Jarvius, M., Xie, Y., . . . Westermark, B. (2016). Clonal Variation in Drug and Radiation Response among Glioma-Initiating Cells Is Linked to Proneural-Mesenchymal Transition. Cell reports, 17(11), 2994-3009
Open this publication in new window or tab >>Clonal Variation in Drug and Radiation Response among Glioma-Initiating Cells Is Linked to Proneural-Mesenchymal Transition
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2016 (English)In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 17, no 11, p. 2994-3009Article in journal (Refereed) Published
Abstract [en]

Intratumoral heterogeneity is a hallmark of glioblastoma multiforme and thought to negatively affect treatment efficacy. Here, we establish libraries of glioma-initiating cell (GIC) clones from patient samples and find extensive molecular and phenotypic variability among clones, including a range of responses to radiation and drugs. This widespread variability was observed as a continuumof multitherapy resistance phenotypes linked to a proneural-mesenchymal shift in the transcriptome. Multitherapy resistance was associated with a semi-stable cell state that was characterized by an altered DNA methylation pattern at promoter regions of mesenchymal master regulators and enhancers. The gradient of cell states within the GIC compartment constitutes a distinct form of heterogeneity. Our findings may open an avenue toward the development of new therapeutic rationales designed to reverse resistant cell states.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-314416 (URN)10.1016/j.celrep.2016.11.056 (DOI)000390894700019 ()
Funder
Knut and Alice Wallenberg Foundation, 2013.0280Swedish Cancer Society, 150670
Available from: 2017-02-08 Created: 2017-02-02 Last updated: 2017-11-29Bibliographically approved
Senkowski, W., Jarvius, M., Rubin, J., Lengqvist, J., Gustafsson, M. G., Nygren, P., . . . Fryknäs, M. (2016). Large-Scale Gene Expression Profiling Platform for Identification of Context-Dependent Drug Responses in Multicellular Tumor Spheroids. CELL CHEMICAL BIOLOGY, 23(11), 1428-1438
Open this publication in new window or tab >>Large-Scale Gene Expression Profiling Platform for Identification of Context-Dependent Drug Responses in Multicellular Tumor Spheroids
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2016 (English)In: CELL CHEMICAL BIOLOGY, ISSN 2451-9448, Vol. 23, no 11, p. 1428-1438Article in journal (Refereed) Published
Abstract [en]

Cancer cell lines grown as two-dimensional (2D) cultures have been an essential model for studying cancer biology and anticancer drug discovery. However, 2D cancer cell cultures have major limitations, as they do not closely mimic the heterogeneity and tissue context of in vivo tumors. Developing three-dimensional (3D) cell cultures, such as multicellular tumor spheroids, has the potential to address some of these limitations. Here, we combined a high-throughput gene expression profiling method with a tumor spheroid-based drug-screening assay to identify context-dependent treatment responses. As a proof of concept, we examined drug responses of quiescent cancer cells to oxidative phosphorylation (OXPHOS) inhibitors. Use of multicellular tumor spheroids led to discovery that the mevalonate pathway is upregulated in quiescent cells during OXPHOS inhibition, and that OXPHOS inhibitors and mevalonate pathway inhibitors were synergistically toxic to quiescent spheroids. This work illustrates how 3D cellular models yield functional and mechanistic insights not accessible via 2D cultures.

National Category
Cell and Molecular Biology Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-311191 (URN)10.1016/j.chembiol.2016.09.013 (DOI)000388373200015 ()27984028 (PubMedID)
Funder
Swedish Cancer SocietySwedish Foundation for Strategic Research
Available from: 2016-12-22 Created: 2016-12-22 Last updated: 2018-01-13Bibliographically approved
Eriksson, A., Gustafsson, M., Fryknäs, M., Gullbo, J., Nygren, P., Höglund, M. & Larsson, R. (2016). Repositioning Of Quinacrine For Treatment Of Acute Myeloid Leukemia - Synergies And In Vivo Effects. Paper presented at 21st Congress of the European-Hematology-Association, JUN 09-12, 2016, Copenhagen, DENMARK. Haematologica, 101, 367-368
Open this publication in new window or tab >>Repositioning Of Quinacrine For Treatment Of Acute Myeloid Leukemia - Synergies And In Vivo Effects
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2016 (English)In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 101, p. 367-368Article in journal, Meeting abstract (Other academic) Published
National Category
Hematology
Identifiers
urn:nbn:se:uu:diva-301452 (URN)000379484601269 ()
Conference
21st Congress of the European-Hematology-Association, JUN 09-12, 2016, Copenhagen, DENMARK
Available from: 2016-08-24 Created: 2016-08-23 Last updated: 2017-11-28Bibliographically approved
Kolosenko, I., Fryknäs, M., Forsberg, S., Johnsson, P., Cheon, H., Holvey-Bates, E. G., . . . De Milito, A. (2015). Cell crowding induces interferon regulatory factor 9, which confers resistance to chemotherapeutic drugs. International Journal of Cancer, 136(4), E51-E61
Open this publication in new window or tab >>Cell crowding induces interferon regulatory factor 9, which confers resistance to chemotherapeutic drugs
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2015 (English)In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 136, no 4, p. E51-E61Article in journal (Refereed) Published
Abstract [en]

The mechanism of multicellular drug resistance, defined as the reduced efficacy of chemotherapeutic drugs in solid tumors is incompletely understood. Here we report that colon carcinoma cells cultured as 3D microtissues (spheroids) display dramatic increases in the expression of a subset of type I interferon-(IFN)-stimulated genes (ISGs). A similar gene signature was associated previously with resistance to radiation and chemotherapy, prompting us to examine the underlying biological mechanisms. Analysis of spheroids formed by different tumor cell lines and studies using knock-down of gene expression showed that cell crowding leads to the induction of IFN regulatory factor-9 (IRF9) which together with STAT2 and independently of IFNs, is necessary for ISG upregulation. Increased expression of IRF9 alone was sufficient to induce the ISG subset in monolayer cells and to confer increased resistance to clinically used cytotoxic drugs. Our data reveal a novel mechanism of regulation of a subset of ISGs, leading to drug resistance in solid tumors. What's new? Drug resistance remains a major challenge in the management of cancer patients. Using a 3D model of tumor cells the authors identify cell crowding and the interferon response as important mediators of drug resistance. They demonstrate that interferon regulatory factor 9 (IRF9) and a panel of interferon-stimulated genes are induced by cell crowding in this model. These results link unexpected new molecular mechanisms with the therapy resistance of solid tumors.

Keyword
multicellular spheroids, IRF9, interferon-stimulated genes, STAT transcription factors, chemoresistance
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-241382 (URN)10.1002/ijc.29161 (DOI)000346089900005 ()25156627 (PubMedID)
Available from: 2015-01-26 Created: 2015-01-12 Last updated: 2017-12-05Bibliographically approved
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