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  1. Article ; Online: Lattice-based model of ductal carcinoma in situ suggests rules for breast cancer progression to an invasive state.

    Eline Boghaert / Derek C Radisky / Celeste M Nelson

    PLoS Computational Biology, Vol 10, Iss 12, p e

    2014  Volume 1003997

    Abstract: Ductal carcinoma in situ (DCIS) is a heterogeneous group of non-invasive lesions of the breast that result from abnormal proliferation of mammary epithelial cells. Pathologists characterize DCIS by four tissue morphologies (micropapillary, cribriform, ... ...

    Abstract Ductal carcinoma in situ (DCIS) is a heterogeneous group of non-invasive lesions of the breast that result from abnormal proliferation of mammary epithelial cells. Pathologists characterize DCIS by four tissue morphologies (micropapillary, cribriform, solid, and comedo), but the underlying mechanisms that distinguish the development and progression of these morphologies are not well understood. Here we explored the conditions leading to the emergence of the different morphologies of DCIS using a two-dimensional multi-cell lattice-based model that incorporates cell proliferation, apoptosis, necrosis, adhesion, and contractility. We found that the relative rates of cell proliferation and apoptosis governed which of the four morphologies emerged. High proliferation and low apoptosis favored the emergence of solid and comedo morphologies. In contrast, low proliferation and high apoptosis led to the micropapillary morphology, whereas high proliferation and high apoptosis led to the cribriform morphology. The natural progression between morphologies cannot be investigated in vivo since lesions are usually surgically removed upon detection; however, our model suggests probable transitions between these morphologies during breast cancer progression. Importantly, cribriform and comedo appear to be the ultimate morphologies of DCIS. Motivated by previous experimental studies demonstrating that tumor cells behave differently depending on where they are located within the mammary duct in vivo or in engineered tissues, we examined the effects of tissue geometry on the progression of DCIS. In agreement with our previous experimental work, we found that cells are more likely to invade from the end of ducts and that this preferential invasion is regulated by cell adhesion and contractility. This model provides additional insight into tumor cell behavior and allows the exploration of phenotypic transitions not easily monitored in vivo.
    Keywords Biology (General) ; QH301-705.5
    Subject code 610
    Language English
    Publishing date 2014-12-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Regulation of Epithelial-Mesenchymal Transition in Breast Cancer Cells by Cell Contact and Adhesion

    Magdalena A. Cichon / Celeste M. Nelson / Derek C. Radisky

    Cancer Informatics, Vol 2015, Iss Suppl. 3, Pp 1-

    2015  Volume 13

    Keywords Neoplasms. Tumors. Oncology. Including cancer and carcinogens ; RC254-282 ; Internal medicine ; RC31-1245 ; Medicine ; R
    Language English
    Publishing date 2015-02-01T00:00:00Z
    Publisher Libertas Academica
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: PRSS3/Mesotrypsin and kallikrein-related peptidase 5 are associated with poor prognosis and contribute to tumor cell invasion and growth in lung adenocarcinoma

    Honghai Ma / Alexandra Hockla / Christine Mehner / Matt Coban / Niv Papo / Derek C. Radisky / Evette S. Radisky

    Scientific Reports, Vol 9, Iss 1, Pp 1-

    2019  Volume 12

    Abstract: Abstract Serine proteases have been implicated as key drivers and facilitators of lung cancer malignancy, and while these proteins represent straightforward targets for therapeutic inhibitors, identification of optimal points for intervention has been ... ...

    Abstract Abstract Serine proteases have been implicated as key drivers and facilitators of lung cancer malignancy, and while these proteins represent straightforward targets for therapeutic inhibitors, identification of optimal points for intervention has been complicated by the complex networks in which these enzymes function. Here we implicate a signaling pathway consisting of PRSS3/mesotrypsin and kallikrein-related peptidase 5 (KLK5) in lung adenocarcinoma malignancy. We show that elevated PRSS3/mesotrypsin expression is prognostic for poor outcome for patients with lung adenocarcinoma, and that genetic or pharmacologic targeting of PRSS3/mesotrypsin reduces lung adenocarcinoma cell invasiveness and proliferation. We further show that genetic targeting of KLK5, a known target of PRSS3/mesotrypsin, phenocopies the effect of PRSS3/mesotrypsin knockdown, and also that elevated expression of KLK5 is similarly prognostic for outcome in lung adenocarcinoma. Finally, we use transcriptional profiling experiments to show that PRSS3/mesotrypsin and KLK5 control a common malignancy-promoting pathway. These experiments implicate a potential PRSS3/mesotrypsin-KLK5 signaling module in lung adenocarcinoma and reveal the potential therapeutic benefit of selectively targeting these pathways.
    Keywords Medicine ; R ; Science ; Q
    Subject code 570
    Language English
    Publishing date 2019-02-01T00:00:00Z
    Publisher Nature Publishing Group
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article: Mechanically patterning the embryonic airway epithelium

    Varner, Victor D / Jason P. Gleghorn / Erin Miller / Derek C. Radisky / Celeste M. Nelson

    Proceedings of the National Academy of Sciences of the United States of America. 2015 July 28, v. 112, no. 30

    2015  

    Abstract: During branching morphogenesis of the developing lung, it is generally thought that a spatial template of biochemical cues determines the airway branching pattern. Here, however, we demonstrate that physical mechanisms can control the pattern of airway ... ...

    Abstract During branching morphogenesis of the developing lung, it is generally thought that a spatial template of biochemical cues determines the airway branching pattern. Here, however, we demonstrate that physical mechanisms can control the pattern of airway branching. Using a combination of 3D culture experiments and theoretical modeling, we show that a growth-induced physical instability initiates the formation of new epithelial branches. Tuning epithelial growth rate controls the dominant wavelength of the instability, and thereby the branching pattern. These findings emphasize the role of mechanical forces during morphogenesis and indicate that lung development is not a closed genetic system. Physical cues also regulate the spatially patterned cell behaviors that underlie organ assembly in the embryo.

    Collections of cells must be patterned spatially during embryonic development to generate the intricate architectures of mature tissues. In several cases, including the formation of the branched airways of the lung, reciprocal signaling between an epithelium and its surrounding mesenchyme helps generate these spatial patterns. Several molecular signals are thought to interact via reaction-diffusion kinetics to create distinct biochemical patterns, which act as molecular precursors to actual, physical patterns of biological structure and function. Here, however, we show that purely physical mechanisms can drive spatial patterning within embryonic epithelia. Specifically, we find that a growth-induced physical instability defines the relative locations of branches within the developing murine airway epithelium in the absence of mesenchyme. The dominant wavelength of this instability determines the branching pattern and is controlled by epithelial growth rates. These data suggest that physical mechanisms can create the biological patterns that underlie tissue morphogenesis in the embryo.
    Keywords branches ; epithelium ; models ; morphogenesis ; wavelengths ; buckling ; instability ; mechanical stress ; morphodynamics
    Language English
    Dates of publication 2015-0728
    Size p. 9230-9235.
    Publishing place National Academy of Sciences
    Document type Article
    ZDB-ID 209104-5
    ISSN 1091-6490 ; 0027-8424
    ISSN (online) 1091-6490
    ISSN 0027-8424
    DOI 10.1073/pnas.1504102112
    Database NAL-Catalogue (AGRICOLA)

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  5. Article ; Online: Somatic mutations in benign breast disease tissues and association with breast cancer risk

    Stacey J. Winham / Chen Wang / Ethan P. Heinzen / Aditya Bhagwate / Yuanhang Liu / Samantha J. McDonough / Melody L. Stallings-Mann / Marlene H. Frost / Robert A. Vierkant / Lori A. Denison / Jodi M. Carter / Mark E. Sherman / Derek C. Radisky / Amy C. Degnim / Julie M. Cunningham

    BMC Medical Genomics, Vol 14, Iss 1, Pp 1-

    2021  Volume 12

    Abstract: Abstract Background Benign breast disease (BBD) is a risk factor for breast cancer (BC); however, little is known about the genetic alterations present at the time of BBD diagnosis and how these relate to risk of incident BC. Methods A subset of a long- ... ...

    Abstract Abstract Background Benign breast disease (BBD) is a risk factor for breast cancer (BC); however, little is known about the genetic alterations present at the time of BBD diagnosis and how these relate to risk of incident BC. Methods A subset of a long-term BBD cohort was selected to examine DNA variation across three BBD groups (42 future estrogen receptor-positive (ER+) BC, 36 future estrogen receptor-negative (ER−) BC, and 42 controls cancer-free for at least 16 years post-BBD). DNA extracted from archival formalin fixed, paraffin-embedded (FFPE) tissue blocks was analyzed for presence of DNA alterations using a targeted panel of 93 BC-associated genes. To address artifacts frequently observed in FFPE tissues (e.g., C>T changes), we applied three filtering strategies based on alternative allele frequencies and nucleotide substitution context. Gene-level associations were performed using two types of burden tests and adjusted for clinical and technical covariates. Results After filtering, the variant frequency of SNPs in our sample was highly consistent with population allele frequencies reported in 1 KG/ExAC (0.986, p < 1e−16). The top ten genes found to be nominally associated with later cancer status by four of 12 association methods(p < 0.05) were MED12, MSH2, BRIP1, PMS1, GATA3, MUC16, FAM175A, EXT2, MLH1 and TGFB1, although these were not statistically significant in permutation testing. However, all 10 gene-level associations had OR < 1 with lower mutation burden in controls compared to cases, which was marginally statistically significant in permutation testing (p = 0.04). Comparing between the three case groups, BBD ER+ cases were closer to controls in mutation profile, while BBD ER− cases were distinct. Notably, the variant burden was significantly higher in controls than in either ER+ or ER− cases. CD45 expression was associated with mutational burden (p < 0.001). Conclusions Somatic mutations were more frequent in benign breast tissue from women who did not develop cancer, opening ...
    Keywords Breast cancer risk ; Benign breast disease ; Somatic mutations ; Mutation burden ; CD45 expression ; Internal medicine ; RC31-1245 ; Genetics ; QH426-470
    Subject code 616 ; 610
    Language English
    Publishing date 2021-07-01T00:00:00Z
    Publisher BMC
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  6. Article ; Online: PEGylation extends circulation half-life while preserving in vitro and in vivo activity of tissue inhibitor of metalloproteinases-1 (TIMP-1).

    Jyotica Batra / Jessica Robinson / Christine Mehner / Alexandra Hockla / Erin Miller / Derek C Radisky / Evette S Radisky

    PLoS ONE, Vol 7, Iss 11, p e

    2012  Volume 50028

    Abstract: Excess proteolytic activity of matrix metalloproteinases (MMPs) contributes to the development of arthritis, cardiovascular diseases and cancer progression, implicating these enzymes as therapeutic targets. While many small molecule inhibitors of MMPs ... ...

    Abstract Excess proteolytic activity of matrix metalloproteinases (MMPs) contributes to the development of arthritis, cardiovascular diseases and cancer progression, implicating these enzymes as therapeutic targets. While many small molecule inhibitors of MMPs have been developed, clinical uses have been limited, in part by toxicity and off-target effects. Development of the endogenous tissue inhibitors of metalloproteinases (TIMPs) as recombinant biopharmaceuticals represents an alternative therapeutic approach; however, the short plasma half-life of recombinant TIMPs has restricted their potential in this arena. To overcome this limitation, we have modified recombinant human TIMP-1 (rhTIMP-1) by PEGylation on lysine residues. We analyzed a mixture of mono- and di-PEGylated rhTIMP-1 species modified by attachment of 20 kDa mPEG chains (PEG(20K)-TIMP-1), as confirmed by SELDI-TOF mass spectrometry. This preparation retained complete inhibitory activity toward the MMP-3 catalytic domain and partial inhibitory activity toward full length MMP-9. Pharmacokinetic evaluation showed that PEGylation extended the plasma half-life of rhTIMP-1 in mice from 1.1 h to 28 h. In biological assays, PEG(20K)-TIMP-1 inhibited both MMP-dependent cancer cell invasion and tumor cell associated gelatinase activity. Overall these results suggest that PEGylated TIMP-1 exhibits improved potential for development as an anti-cancer recombinant protein therapeutic, and additionally may offer potential for clinical applications in the treatment of other diseases.
    Keywords Medicine ; R ; Science ; Q
    Subject code 610
    Language English
    Publishing date 2012-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  7. Article ; Online: An integrated model of the transcriptome of HER2-positive breast cancer.

    Krishna R Kalari / Brian M Necela / Xiaojia Tang / Kevin J Thompson / Melissa Lau / Jeanette E Eckel-Passow / Jennifer M Kachergus / S Keith Anderson / Zhifu Sun / Saurabh Baheti / Jennifer M Carr / Tiffany R Baker / Poulami Barman / Derek C Radisky / Richard W Joseph / Sarah A McLaughlin / High-seng Chai / Stephan Camille / David Rossell /
    Yan W Asmann / E Aubrey Thompson / Edith A Perez

    PLoS ONE, Vol 8, Iss 11, p e

    2013  Volume 79298

    Abstract: Our goal in these analyses was to use genomic features from a test set of primary breast tumors to build an integrated transcriptome landscape model that makes relevant hypothetical predictions about the biological and/or clinical behavior of HER2- ... ...

    Abstract Our goal in these analyses was to use genomic features from a test set of primary breast tumors to build an integrated transcriptome landscape model that makes relevant hypothetical predictions about the biological and/or clinical behavior of HER2-positive breast cancer. We interrogated RNA-Seq data from benign breast lesions, ER+, triple negative, and HER2-positive tumors to identify 685 differentially expressed genes, 102 alternatively spliced genes, and 303 genes that expressed single nucleotide sequence variants (eSNVs) that were associated with the HER2-positive tumors in our survey panel. These features were integrated into a transcriptome landscape model that identified 12 highly interconnected genomic modules, each of which represents a cellular processes pathway that appears to define the genomic architecture of the HER2-positive tumors in our test set. The generality of the model was confirmed by the observation that several key pathways were enriched in HER2-positive TCGA breast tumors. The ability of this model to make relevant predictions about the biology of breast cancer cells was established by the observation that integrin signaling was linked to lapatinib sensitivity in vitro and strongly associated with risk of relapse in the NCCTG N9831 adjuvant trastuzumab clinical trial dataset. Additional modules from the HER2 transcriptome model, including ubiquitin-mediated proteolysis, TGF-beta signaling, RHO-family GTPase signaling, and M-phase progression, were linked to response to lapatinib and paclitaxel in vitro and/or risk of relapse in the N9831 dataset. These data indicate that an integrated transcriptome landscape model derived from a test set of HER2-positive breast tumors has potential for predicting outcome and for identifying novel potential therapeutic strategies for this breast cancer subtype.
    Keywords Medicine ; R ; Science ; Q
    Subject code 616
    Language English
    Publishing date 2013-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  8. Article: Mechanically patterning the embryonic airway epithelium

    Varner, Victor D. / Jason P. Gleghorn / Erin Miller / Derek C. Radisky / Celeste M. Nelson

    Proceedings of the National Academy of Sciences of the United States of America

    Volume v. 112,, Issue no. 3

    Abstract: During branching morphogenesis of the developing lung, it is generally thought that a spatial template of biochemical cues determines the airway branching pattern. Here, however, we demonstrate that physical mechanisms can control the pattern of airway ... ...

    Abstract During branching morphogenesis of the developing lung, it is generally thought that a spatial template of biochemical cues determines the airway branching pattern. Here, however, we demonstrate that physical mechanisms can control the pattern of airway branching. Using a combination of 3D culture experiments and theoretical modeling, we show that a growth-induced physical instability initiates the formation of new epithelial branches. Tuning epithelial growth rate controls the dominant wavelength of the instability, and thereby the branching pattern. These findings emphasize the role of mechanical forces during morphogenesis and indicate that lung development is not a closed genetic system. Physical cues also regulate the spatially patterned cell behaviors that underlie organ assembly in the embryo.
    Language English
    Document type Article
    ISSN 0027-8424
    Database AGRIS - International Information System for the Agricultural Sciences and Technology

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