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Nilsson, Mats
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Publications (10 of 103) Show all publications
Strell, C., Paulsson, J., Jin, S.-B., Tobin, N. P., Mezheyeuski, A., Roswall, P., . . . Ostman, A. (2019). Impact of Epithelial-Stromal Interactions on Peritumoral Fibroblasts in Ductal Carcinoma in Situ. Journal of the National Cancer Institute, 111(9), 983-995, Article ID djy234.
Open this publication in new window or tab >>Impact of Epithelial-Stromal Interactions on Peritumoral Fibroblasts in Ductal Carcinoma in Situ
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2019 (English)In: Journal of the National Cancer Institute, ISSN 0027-8874, E-ISSN 1460-2105, Vol. 111, no 9, p. 983-995, article id djy234Article in journal (Refereed) Published
Abstract [en]

Background: A better definition of biomarkers and biological processes related to local recurrence and disease progression is highly warranted for ductal breast carcinoma in situ (DCIS). Stromal-epithelial interactions are likely of major importance for the biological, clinical, and pathological distinctions between high- and low-risk DCIS cases. Methods: Stromal platelet derived growth factor receptor (PDGFR) was immunohistochemically assessed in two DCIS patient cohorts (n = 458 and n = 80). Cox proportional hazards models were used to calculate the hazard ratios of recurrence. The molecular mechanisms regulating stromal PDGFR expression were investigated in experimental in vitro co-culture systems of DCIS cells and fibroblasts and analyzed using immunoblot and quantitative real-time PCR. Knock-out of JAG1 in DCIS cells and NOTCH2 in fibroblasts was obtained through CRISPR/Cas9. Experimental data were validated by mammary fat pad injection of DCIS and DCIS-JAG1 knock-out cells (10 mice per group). All statistical tests were two-sided. Results: PDGFR alpha((low))/PDGFR beta((high)) fibroblasts were associated with increased risk for recurrence in DCIS (univariate hazard ratio = 1.59, 95% confidence interval [CI] = 1.02 to 2.46; P = .04 Wald test; multivariable hazard ratio = 1.78, 95% CI = 1.07 to 2.97; P = .03). Tissue culture and mouse model studies indicated that this fibroblast phenotype is induced by DCIS cells in a cell contact-dependent manner. Epithelial Jagged1 and fibroblast Notch2 were identified through loss-of-function studies as key juxtacrine signaling components driving the formation of the poor prognosis-associated fibroblast phenotype. Conclusions: A PDGFR alpha((low))/PDGFR beta((high)) fibroblast subset was identified as a marker for high-risk DCIS. The Jagged-1/Notch2/PDGFR stroma-epithelial pathway was described as a novel signaling mechanism regulating this poor prognosis-associated fibroblast subset. In general terms, the study highlights epithelial-stromal crosstalk in DCIS and contributes to ongoing efforts to define clinically relevant fibroblast subsets and their etiology.

National Category
Cancer and Oncology Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-397124 (URN)10.1093/jnci/djy234 (DOI)000493067400014 ()30816935 (PubMedID)
Funder
Swedish Cancer Society, 150895Swedish Research Council, Diarienr 349-2006-160The Cancer Research Funds of Radiumhemmet
Available from: 2019-11-29 Created: 2019-11-29 Last updated: 2019-11-29Bibliographically approved
Salamon, J., Qian, X., Nilsson, M. & Lynn, D. J. (2018). Network Visualization and Analysis of Spatially Aware Gene Expression Data with InsituNet. Cell Systems, 6(5), 626-630.E3
Open this publication in new window or tab >>Network Visualization and Analysis of Spatially Aware Gene Expression Data with InsituNet
2018 (English)In: Cell Systems, ISSN 2405-4712, Vol. 6, no 5, p. 626-630.E3Article in journal (Refereed) Published
Abstract [en]

In situ sequencing methods generate spatially resolved RNA localization and expression data at an almost single-cell resolution. Few methods, however, currently exist to analyze and visualize the complex data that is produced, which can encode the localization and expression of a million or more individual transcripts in a tissue section. Here, we present InsituNet, an application that converts in situ sequencing data into interactive network-based visualizations, where each unique transcript is a node in the network and edges represent the spatial co-expression relationships between transcripts. InsituNet is available as an app for the Cytoscape platform at http://apps.cytoscape.org/apps/insitunet. InsituNet enables the analysis of the relationships that exist between these transcripts and can uncover how spatial co-expression profiles change in different regions of the tissue or across different tissue sections.

Place, publisher, year, edition, pages
CELL PRESS, 2018
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-357567 (URN)10.1016/j.cels.2018.03.010 (DOI)000433906700011 ()29753646 (PubMedID)
Funder
EU, FP7, Seventh Framework Programme, FP7-HEALTH-2011-278568
Available from: 2018-08-17 Created: 2018-08-17 Last updated: 2018-09-26Bibliographically approved
Wu, C., Simonetti, M., Rossell, C., Mignardi, M., Mirzazadeh, R., Annaratone, L., . . . Nilsson, M. (2018). RollFISH achieves robust quantification of single-molecule RNA biomarkers in paraffin-embedded tumor tissue samples. COMMUNICATIONS BIOLOGY, 1, Article ID 209.
Open this publication in new window or tab >>RollFISH achieves robust quantification of single-molecule RNA biomarkers in paraffin-embedded tumor tissue samples
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2018 (English)In: COMMUNICATIONS BIOLOGY, ISSN 2399-3642, Vol. 1, article id 209Article in journal (Refereed) Published
Abstract [en]

Single-molecule RNA fluorescence in situ hybridization (smFISH) represents a promising approach to quantify the expression of clinically useful biomarkers in tumor samples. However, routine application of smFISH to formalin-fixed, paraffin-embedded (FFPE) samples is challenging due to the low signal intensity and high background noise. Here we present RollFISH, a method combining the specificity of smFISH with the signal boosting of rolling circle amplification. We apply RollFISH to quantify widely used breast cancer biomarkers in cell lines and FFPE samples. Thanks to the high signal-to-noise ratio, we can visualize selected biomarkers at low magnification (20 x) across entire tissue sections, and thus assess their spatial heterogeneity. Lastly, we apply RollFISH to quantify HER2 mRNA in 150 samples on a single tissue microarray, achieving a sensitivity and specificity of detection of HER2-positive samples of similar to 90%. RollFISH is a robust method for quantifying the expression and intratumor heterogeneity of biomarkers in FFPE tissues.

Place, publisher, year, edition, pages
Nature Publishing Group, 2018
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-380510 (URN)10.1038/s42003-018-0218-0 (DOI)000461126500208 ()30511022 (PubMedID)
Funder
Swedish Research Council, 521-2014-2866Swedish Research Council, 2014-3380Swedish Foundation for Strategic Research , BD15-0095Swedish Cancer Society, CAN 2015/585Swedish Cancer Society, CAN 2015/838Swedish Society for Medical Research (SSMF)Science for Life Laboratory - a national resource center for high-throughput molecular bioscience
Available from: 2019-04-11 Created: 2019-04-11 Last updated: 2019-04-11Bibliographically approved
Schuette, M., Risch, T., Abdavi-Azar, N., Boehnke, K., Schumacher, D., Keil, M., . . . Yaspo, M.-L. (2017). Molecular dissection of colorectal cancer in pre-clinical models identifies biomarkers predicting sensitivity to EGFR inhibitors. Nature Communications, 8, Article ID 14262.
Open this publication in new window or tab >>Molecular dissection of colorectal cancer in pre-clinical models identifies biomarkers predicting sensitivity to EGFR inhibitors
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2017 (English)In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 8, article id 14262Article in journal (Refereed) Published
Abstract [en]

Colorectal carcinoma represents a heterogeneous entity, with only a fraction of the tumours responding to available therapies, requiring a better molecular understanding of the disease in precision oncology. To address this challenge, the OncoTrack consortium recruited 106 CRC patients (stages I-IV) and developed a pre-clinical platform generating a compendium of drug sensitivity data totalling 44,000 assays testing 16 clinical drugs on patient-derived in vivo and in vitro models. This large biobank of 106 tumours, 35 organoids and 59 xenografts, with extensive omics data comparing donor tumours and derived models provides a resource for advancing our understanding of CRC. Models recapitulate many of the genetic and transcriptomic features of the donors, but defined less complex molecular sub-groups because of the loss of human stroma. Linking molecular profiles with drug sensitivity patterns identifies novel biomarkers, including a signature outperforming RAS/RAF mutations in predicting sensitivity to the EGFR inhibitor cetuximab.

National Category
Cancer and Oncology Genetics
Identifiers
urn:nbn:se:uu:diva-316929 (URN)10.1038/ncomms14262 (DOI)000393656400001 ()28186126 (PubMedID)
Funder
Swedish Research CouncilVINNOVAEU, European Research Council
Available from: 2017-03-09 Created: 2017-03-09 Last updated: 2017-11-29Bibliographically approved
Kühnemund, M., Hernandez-Neuta, I., Sharif, M. I., Cornaglia, M., Gijs, M. A. M. & Nilsson, M. (2017). Sensitive and inexpensive digital DNA analysis by microfluidic enrichment of rolling circle amplified single-molecules. Nucleic Acids Research, 45(8), Article ID e59.
Open this publication in new window or tab >>Sensitive and inexpensive digital DNA analysis by microfluidic enrichment of rolling circle amplified single-molecules
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2017 (English)In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 45, no 8, article id e59Article in journal (Refereed) Published
Abstract [en]

Single molecule quantification assays provide the ultimate sensitivity and precision for molecular analysis. However, most digital analysis techniques, i.e. droplet PCR, require sophisticated and expensive instrumentation for molecule compartmentalization, amplification and analysis. Rolling circle amplification (RCA) provides a simpler means for digital analysis. Nevertheless, the sensitivity of RCA assays has until now been limited by inefficient detection methods. We have developed a simple microfluidic strategy for enrichment of RCA products into a single field of view of a low magnification fluorescent sensor, enabling ultra-sensitive digital quantification of nucleic acids over a dynamic range from 1.2 aM to 190 fM. We prove the broad applicability of our analysis platform by demonstrating 5-plex detection of as little as similar to 1 pg (similar to 300 genome copies) of pathogenic DNA with simultaneous antibiotic resistance marker detection, and the analysis of rare oncogene mutations. Our method is simpler, more cost-effective and faster than other digital analysis techniques and provides the means to implement digital analysis in any laboratory equipped with a standard fluorescent microscope.

National Category
Biochemistry and Molecular Biology Microbiology in the medical area
Identifiers
urn:nbn:se:uu:diva-322522 (URN)10.1093/nar/gkw1324 (DOI)000400578600004 ()28077562 (PubMedID)
Funder
EU, FP7, Seventh Framework Programme, 264737Swedish Foundation for Strategic Research , SBE13-0125Swedish Research CouncilSwedish Research Council Formas, 221-2011-1692EU, Horizon 2020, 115843
Note

De 2 första författarna delar förstaförfattarskapet.

Available from: 2017-05-23 Created: 2017-05-23 Last updated: 2018-01-13Bibliographically approved
Kühnemund, M., Wei, Q., Darai, E., Wang, Y., Hernandez-Neuta, I., Yang, Z., . . . Nilsson, M. (2017). Targeted DNA sequencing and in situ mutation analysis using mobile phone microscopy. Nature Communications, 8, Article ID 13913.
Open this publication in new window or tab >>Targeted DNA sequencing and in situ mutation analysis using mobile phone microscopy
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2017 (English)In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 8, article id 13913Article in journal (Refereed) Published
Abstract [en]

Molecular diagnostics is typically outsourced to well-equipped centralized laboratories, often far from the patient. We developed molecular assays and portable optical imaging designs that permit on-site diagnostics with a cost-effective mobile-phone-based multimodal microscope. We demonstrate that targeted next-generation DNA sequencing reactions and in situ point mutation detection assays in preserved tumour samples can be imaged and analysed using mobile phone microscopy, achieving a new milestone for tele-medicine technologies.

National Category
Biomedical Laboratory Science/Technology
Identifiers
urn:nbn:se:uu:diva-315810 (URN)10.1038/ncomms13913 (DOI)000391931300001 ()28094784 (PubMedID)
Funder
Swedish Research CouncilSwedish Cancer Society, 2015/838 2015/629Science for Life Laboratory - a national resource center for high-throughput molecular bioscience
Available from: 2017-02-22 Created: 2017-02-22 Last updated: 2017-11-29Bibliographically approved
Carinelli, S., Kühnemund, M., Nilsson, M. & Pividori, M. I. (2017). Yoctomole electrochemical genosensing of Ebola virus cDNA by rolling circle and circle to circle amplification. Paper presented at 26th Anniversary World Congress on Biosensors (Biosensors), MAY 24-28, 2016, Gothenburg, SWEDEN. Biosensors & bioelectronics, 93, 65-71
Open this publication in new window or tab >>Yoctomole electrochemical genosensing of Ebola virus cDNA by rolling circle and circle to circle amplification
2017 (English)In: Biosensors & bioelectronics, ISSN 0956-5663, E-ISSN 1873-4235, Vol. 93, p. 65-71Article in journal (Refereed) Published
Abstract [en]

This work addresses the design of an Ebola diagnostic test involving a simple, rapid, specific and highly sensitive procedure based on isothermal amplification on magnetic particles with electrochemical readout. Ebola padlock probes were designed to detect a specific L-gene sequence present in the five most common Ebola species. Ebola cDNA was amplified by rolling circle amplification (RCA) on magnetic particles. Further re-amplification was performed by circle-to-circle amplification (C2CA) and the products were detected in a double-tagging approach using a biotinylated capture probe for immobilization on magnetic particles and a readout probe for electrochemical detection by square-wave voltammetry on commercial screen-printed electrodes. The electrochemical genosensor was able to detect as low as 200 ymol, corresponding to 120 cDNA molecules of L-gene Ebola virus with a limit of detection of 33 cDNA molecules. The isothermal double-amplification procedure by C2CA combined with the electrochemical readout and the magnetic actuation enables the high sensitivity, resulting in a rapid, inexpensive, robust and user-friendly sensing strategy that offers a promising approach for the primary care in low resource settings, especially in less developed countries.

Keywords
Ebola virus, Electrochemical genosensing, Magnetic particle, Isothermal amplification, Circle-to-circle amplification
National Category
Medical Biotechnology
Identifiers
urn:nbn:se:uu:diva-322442 (URN)10.1016/j.bios.2016.09.099 (DOI)000399259000011 ()27838201 (PubMedID)
Conference
26th Anniversary World Congress on Biosensors (Biosensors), MAY 24-28, 2016, Gothenburg, SWEDEN
Available from: 2017-05-23 Created: 2017-05-23 Last updated: 2017-05-23Bibliographically approved
McGinn, S., Bauer, D., Brefort, T., Dong, L., El-Sagheer, A., Elsharawy, A., . . . Gut, I. G. (2016). New technologies for DNA analysis: a review of the READNA Project. New Biotechnology, 33(3), 311-330
Open this publication in new window or tab >>New technologies for DNA analysis: a review of the READNA Project
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2016 (English)In: New Biotechnology, ISSN 1871-6784, E-ISSN 1876-4347, Vol. 33, no 3, p. 311-330Article, review/survey (Refereed) Published
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Research subject
Computerized Image Processing
Identifiers
urn:nbn:se:uu:diva-279724 (URN)10.1016/j.nbt.2015.10.003 (DOI)000373545600001 ()26514324 (PubMedID)
Funder
EU, European Research Council, HEALTH-F4-2008-201418
Available from: 2015-10-26 Created: 2016-03-03 Last updated: 2017-11-30Bibliographically approved
Kuhnemund, M. & Nilsson, M. (2015). Digital quantification of rolling circle amplified single DNA molecules in a resistive pulse sensing nanopore. Biosensors & bioelectronics, 67(SI), 11-17
Open this publication in new window or tab >>Digital quantification of rolling circle amplified single DNA molecules in a resistive pulse sensing nanopore
2015 (English)In: Biosensors & bioelectronics, ISSN 0956-5663, E-ISSN 1873-4235, Vol. 67, no SI, p. 11-17Article in journal (Refereed) Published
Abstract [en]

Novel portable, sensitive and selective DNA sensor methods for bio-sensing applications are required that can rival conventionally used non-portable and expensive fluorescence-based sensors. In this paper, rolling circle amplification (RCA) products are detected in solution and on magnetic particles using a resistive pulse sensing (RPS) nanopore. Low amounts of DNA molecules are detected by padlock probes which are circularized in a strictly target dependent ligation reaction. The DNA-padlock probe-complex is captured on magnetic particles by sequence specific capture oligonucleotides and amplified by a short RCA. Subsequent RPS analysis is used to identify individual particles with single attached RCA products from blank particles. This proof of concept opens up for a novel non-fluorescent digital DNA quantification method that can have many applications in bio-sensing and diagnostic approaches.

Keywords
Padlock probe, RCA, Single molecule detection, Resistive pulse sensing, Nanopore
National Category
Biological Sciences
Identifiers
urn:nbn:se:uu:diva-248795 (URN)10.1016/j.bios.2014.06.040 (DOI)000350076900003 ()25000851 (PubMedID)
Available from: 2015-04-10 Created: 2015-04-08 Last updated: 2017-12-04Bibliographically approved
Russell, C., Roy, S., Ganguly, S., Qian, X., Caruthers, M. H. & Nilsson, M. (2015). Formation of Silver Nanostructures by Rolling Circle Amplification Using Boranephosphonate-Modified Nucleotides. Analytical Chemistry, 87(13), 6660-6666
Open this publication in new window or tab >>Formation of Silver Nanostructures by Rolling Circle Amplification Using Boranephosphonate-Modified Nucleotides
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2015 (English)In: Analytical Chemistry, ISSN 0003-2700, E-ISSN 1520-6882, Vol. 87, no 13, p. 6660-6666Article in journal (Refereed) Published
Abstract [en]

We investigate the efficiency of incorporation of boranephosphonate-modified nucleotides by phi29 DNA poly, merase and present a simple method for forming large defined silver nanostructures by rolling circle amplification (RCA) using boranephosphonate internudeotide linkages. RCA is a linear DNA amplification technique that can use specifically circularized DNA probes for detection of target nucleic acids and proteins. The resulting product is a collapsed single-stranded DNA molecule with tandem repeats of the DNA probe. By substituting each of the natural nucleotides with the corresponding 5'-(alpha-P-borano)-deoxynudeosidetriphosphate, only a small reduction in amplification rate is observed. Also, by substituting all four natural nucleotides, it is possible to enzymatically synthesize a micrometensized, single-stranded DNA molecule with only boranephosphonate internucleotide linkages. Well-defined silver particles are then readily formed along the rolling circle product.

National Category
Analytical Chemistry
Identifiers
urn:nbn:se:uu:diva-260302 (URN)10.1021/acs.analchem.5b00783 (DOI)000357839700037 ()26059318 (PubMedID)
Funder
VINNOVASwedish Research Council
Available from: 2015-08-20 Created: 2015-08-18 Last updated: 2017-12-04Bibliographically approved
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