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  1. Article ; Online: YAP regulates S-phase entry in endothelial cells.

    Zhewei Shen / Ben Z Stanger

    PLoS ONE, Vol 10, Iss 1, p e

    2015  Volume 0117522

    Abstract: The Hippo pathway regulates cell proliferation and apoptosis through the Yes-associated protein (YAP) transcriptional activator. YAP has a well-described role in promoting cell proliferation and survival, but the precise mechanisms and transcriptional ... ...

    Abstract The Hippo pathway regulates cell proliferation and apoptosis through the Yes-associated protein (YAP) transcriptional activator. YAP has a well-described role in promoting cell proliferation and survival, but the precise mechanisms and transcriptional targets that underlie these properties are still unclear and likely context-dependent. We found, using siRNA-mediated knockdown, that YAP is required for proliferation in endothelial cells but not HeLa cells. Specifically, YAP is required for S-phase entry and its absence causes cells to accumulate in G1. Microarray analysis suggests that YAP mediates this effect by regulating the transcription of genes involved in the assembly and/or firing of replication origins and homologous recombination of DNA. These findings thus provide insight into the molecular mechanisms by which YAP regulates cell cycle progression.
    Keywords Medicine ; R ; Science ; Q
    Language English
    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: Dissecting phenotypic transitions in metastatic disease via photoconversion-based isolation

    Yogev Sela / Jinyang Li / Paola Kuri / Allyson J Merrell / Ning Li / Chris Lengner / Pantelis Rompolas / Ben Z Stanger

    eLife, Vol

    2021  Volume 10

    Abstract: Cancer patients often harbor occult metastases, a potential source of relapse that is targetable only through systemic therapy. Studies of this occult fraction have been limited by a lack of tools with which to isolate discrete cells on spatial grounds. ... ...

    Abstract Cancer patients often harbor occult metastases, a potential source of relapse that is targetable only through systemic therapy. Studies of this occult fraction have been limited by a lack of tools with which to isolate discrete cells on spatial grounds. We developed PIC-IT, a photoconversion-based isolation technique allowing efficient recovery of cell clusters of any size – including single-metastatic cells – which are largely inaccessible otherwise. In a murine pancreatic cancer model, transcriptional profiling of spontaneously arising microcolonies revealed phenotypic heterogeneity, functionally reduced propensity to proliferate and enrichment for an inflammatory-response phenotype associated with NF-κB/AP-1 signaling. Pharmacological inhibition of NF-κB depleted microcolonies but had no effect on macrometastases, suggesting microcolonies are particularly dependent on this pathway. PIC-IT thus enables systematic investigation of metastatic heterogeneity. Moreover, the technique can be applied to other biological systems in which isolation and characterization of spatially distinct cell populations is not currently feasible.
    Keywords cell isolation ; metastasis ; photoconversion ; Medicine ; R ; Science ; Q ; Biology (General) ; QH301-705.5
    Subject code 610
    Language English
    Publishing date 2021-02-01T00:00:00Z
    Publisher eLife Sciences Publications Ltd
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Echoes of the embryo

    Nicole M. Aiello / Ben Z. Stanger

    Disease Models & Mechanisms, Vol 9, Iss 2, Pp 105-

    using the developmental biology toolkit to study cancer

    2016  Volume 114

    Abstract: The hallmark of embryonic development is regulation – the tendency for cells to find their way into organized and ‘well behaved’ structures – whereas cancer is characterized by dysregulation and disorder. At face value, cancer biology and developmental ... ...

    Abstract The hallmark of embryonic development is regulation – the tendency for cells to find their way into organized and ‘well behaved’ structures – whereas cancer is characterized by dysregulation and disorder. At face value, cancer biology and developmental biology would thus seem to have little to do with each other. But if one looks beneath the surface, embryos and cancers share a number of cellular and molecular features. Embryos arise from a single cell and undergo rapid growth involving cell migration and cell-cell interactions: features that are also seen in the context of cancer. Consequently, many of the experimental tools that have been used to study embryogenesis for over a century are well-suited to studying cancer. This article will review the similarities between embryogenesis and cancer progression and discuss how some of the concepts and techniques used to understand embryos are now being adapted to provide insight into tumorigenesis, from the origins of cancer cells to metastasis.
    Keywords Cancer ; Embryology ; Intravital imaging ; Lineage tracing ; Reprogramming ; Medicine ; R ; Pathology ; RB1-214
    Subject code 612
    Language English
    Publishing date 2016-02-01T00:00:00Z
    Publisher The Company of Biologists
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: RETRACTED ARTICLE

    Jeffrey Patterson-Fortin / Heta Jadhav / Constantia Pantelidou / Tin Phan / Carter Grochala / Anita K. Mehta / Jennifer L. Guerriero / Gerburg M. Wulf / Brian M. Wolpin / Ben Z. Stanger / Andrew J. Aguirre / James M. Cleary / Alan D. D’Andrea / Geoffrey I. Shapiro

    Nature Communications, Vol 14, Iss 1, Pp 1-

    Polymerase θ inhibition activates the cGAS-STING pathway and cooperates with immune checkpoint blockade in models of BRCA-deficient cancer

    2023  Volume 16

    Abstract: Abstract Recently developed inhibitors of polymerase theta (POLθ) have demonstrated synthetic lethality in BRCA-deficient tumor models. To examine the contribution of the immune microenvironment to antitumor efficacy, we characterized the effects of POLθ ...

    Abstract Abstract Recently developed inhibitors of polymerase theta (POLθ) have demonstrated synthetic lethality in BRCA-deficient tumor models. To examine the contribution of the immune microenvironment to antitumor efficacy, we characterized the effects of POLθ inhibition in immunocompetent models of BRCA1-deficient triple-negative breast cancer (TNBC) or BRCA2-deficient pancreatic ductal adenocarcinoma (PDAC). We demonstrate that genetic POLQ depletion or pharmacological POLθ inhibition induces both innate and adaptive immune responses in these models. POLθ inhibition resulted in increased micronuclei, cGAS/STING pathway activation, type I interferon gene expression, CD8+ T cell infiltration and activation, local paracrine activation of dendritic cells and upregulation of PD-L1 expression. Depletion of CD8+ T cells compromised the efficacy of POLθ inhibition, whereas antitumor effects were augmented in combination with anti-PD-1 immunotherapy. Collectively, our findings demonstrate that POLθ inhibition induces immune responses in a cGAS/STING-dependent manner and provide a rationale for combining POLθ inhibition with immune checkpoint blockade for the treatment of HR-deficient cancers.
    Keywords Science ; Q
    Subject code 616
    Language English
    Publishing date 2023-03-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: Retraction Note

    Jeffrey Patterson-Fortin / Heta Jadhav / Constantia Pantelidou / Tin Phan / Carter Grochala / Anita K. Mehta / Jennifer L. Guerriero / Gerburg M. Wulf / Brian M. Wolpin / Ben Z. Stanger / Andrew J. Aguirre / James M. Cleary / Alan D. D’Andrea / Geoffrey I. Shapiro

    Nature Communications, Vol 14, Iss 1, Pp 1-

    Polymerase θ inhibition activates the cGAS-STING pathway and cooperates with immune checkpoint blockade in models of BRCA-deficient cancer

    2023  Volume 1

    Keywords Science ; Q
    Language English
    Publishing date 2023-12-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  6. Article ; Online: SWIP—a stabilized window for intravital imaging of the murine pancreas

    Wei Du / Christian Adkisson / Xianjun Ye / Camille L. Duran / Benson Chellakkan Selvanesan / Claudia Gravekamp / Maja H. Oktay / John C. McAuliffe / John S. Condeelis / Nicole C. Panarelli / Robert J. Norgard / Yogev Sela / Ben Z. Stanger / David Entenberg

    Open Biology, Vol 12, Iss

    2022  Volume 6

    Abstract: Pancreatitis and pancreatic ductal adenocarcinoma (PDAC) are grave illnesses with high levels of morbidity and mortality. Intravital imaging (IVI) is a powerful technique for visualizing physiological processes in both health and disease. However, the ... ...

    Abstract Pancreatitis and pancreatic ductal adenocarcinoma (PDAC) are grave illnesses with high levels of morbidity and mortality. Intravital imaging (IVI) is a powerful technique for visualizing physiological processes in both health and disease. However, the application of IVI to the murine pancreas presents significant challenges, as it is a deep, compliant, visceral organ that is difficult to access, easily damaged and susceptible to motion artefacts. Existing imaging windows for stabilizing the pancreas during IVI have unfortunately shown poor stability for time-lapsed imaging on the minutes to hours scale, or are unable to accommodate both the healthy and tumour-bearing pancreata. To address these issues, we developed an improved stabilized window for intravital imaging of the pancreas (SWIP), which can be applied to not only the healthy pancreas but also to solid tumours like PDAC. Here, we validate the SWIP and use it to visualize a variety of processes for the first time, including (1) single-cell dynamics within the healthy pancreas, (2) transformation from healthy pancreas to acute pancreatitis induced by cerulein, and (3) the physiology of PDAC in both autochthonous and orthotopically injected models. SWIP can not only improve the imaging stability but also expand the application of IVI in both benign and malignant pancreas diseases.
    Keywords intravital imaging ; pancreatic ductal adenocarcinoma ; pancreatitis ; cerulein ; Biology (General) ; QH301-705.5
    Subject code 610
    Language English
    Publishing date 2022-06-01T00:00:00Z
    Publisher The Royal Society
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  7. Article ; Online: Transcriptional profiling of single tumour cells from pleural effusions reveals heterogeneity of epithelial to mesenchymal transition and extra‐cellular matrix marker expression

    Moen Sen / Ryan M. Hausler / Keely Dulmage / Taylor A. Black / William Murphy / Charles H. Pletcher Jr / Ling Wang / Chang Chen / Stephanie S. Yee / Scott J. Bornheimer / Kara N. Maxwell / Ben Z. Stanger / Jonni S. Moore / Jeffrey C. Thompson / Erica L. Carpenter

    Clinical and Translational Medicine, Vol 12, Iss 7, Pp n/a-n/a (2022)

    2022  

    Keywords Medicine (General) ; R5-920
    Language English
    Publishing date 2022-07-01T00:00:00Z
    Publisher Wiley
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  8. Article ; Online: Mapping and modeling human colorectal carcinoma interactions with the tumor microenvironment

    Ning Li / Qin Zhu / Yuhua Tian / Kyung Jin Ahn / Xin Wang / Zvi Cramer / Justine Jou / Ian W. Folkert / Pengfei Yu / Stephanie Adams-Tzivelekidis / Priyanka Sehgal / Najia N. Mahmoud / Cary B. Aarons / Robert E. Roses / Andrei Thomas-Tikhonenko / Emma E. Furth / Ben Z. Stanger / Anil Rustgi / Malay Haldar /
    Bryson W. Katona / Kai Tan / Christopher J. Lengner

    Nature Communications, Vol 14, Iss 1, Pp 1-

    2023  Volume 17

    Abstract: Abstract The initiation and progression of cancer are intricately linked to the tumor microenvironment (TME). Understanding the function of specific cancer-TME interactions poses a major challenge due in part to the complexity of the in vivo ... ...

    Abstract Abstract The initiation and progression of cancer are intricately linked to the tumor microenvironment (TME). Understanding the function of specific cancer-TME interactions poses a major challenge due in part to the complexity of the in vivo microenvironment. Here we predict cancer-TME interactions from single cell transcriptomic maps of both human colorectal cancers (CRCs) and mouse CRC models, ask how these interactions are altered in human tumor organoid (tumoroid) cultures, and functionally recapitulate human myeloid-carcinoma interactions in vitro. Tumoroid cultures suppress gene expression programs involved in inflammation and immune cell migration, providing a reductive platform for re-establishing carcinoma-immune cell interactions in vitro. Introduction of human monocyte-derived macrophages into tumoroid cultures instructs macrophages to acquire immunosuppressive and pro-tumorigenic gene expression programs similar to those observed in vivo. This includes hallmark induction of SPP1, encoding Osteopontin, an extracellular CD44 ligand with established oncogenic effects. Taken together, these findings offer a framework for understanding CRC-TME interactions and provide a reductionist tool for modeling specific aspects of these interactions.
    Keywords Science ; Q
    Language English
    Publishing date 2023-11-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  9. Article ; Online: Activation of G protein-coupled estrogen receptor signaling inhibits melanoma and improves response to immune checkpoint blockade

    Christopher A Natale / Jinyang Li / Junqian Zhang / Ankit Dahal / Tzvete Dentchev / Ben Z Stanger / Todd W Ridky

    eLife, Vol

    2018  Volume 7

    Abstract: Female sex and history of prior pregnancies are associated with favorable melanoma outcomes. Here, we show that much of the melanoma protective effect likely results from estrogen signaling through the G protein-coupled estrogen receptor (GPER) on ... ...

    Abstract Female sex and history of prior pregnancies are associated with favorable melanoma outcomes. Here, we show that much of the melanoma protective effect likely results from estrogen signaling through the G protein-coupled estrogen receptor (GPER) on melanocytes. Selective GPER activation in primary melanocytes and melanoma cells induced long-term changes that maintained a more differentiated cell state as defined by increased expression of well-established melanocyte differentiation antigens, increased pigment production, decreased proliferative capacity, and decreased expression of the oncodriver and stem cell marker c-Myc. GPER signaling also rendered melanoma cells more vulnerable to immunotherapy. Systemically delivered GPER agonist was well tolerated, and cooperated with immune checkpoint blockade in melanoma-bearing mice to dramatically extend survival, with up to half of mice clearing their tumor. Complete responses were associated with immune memory that protected against tumor rechallenge. GPER may be a useful, pharmacologically accessible target for melanoma.
    Keywords GPER ; GPCR ; melanoma ; Medicine ; R ; Science ; Q ; Biology (General) ; QH301-705.5
    Subject code 570
    Language English
    Publishing date 2018-01-01T00:00:00Z
    Publisher eLife Sciences Publications Ltd
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  10. Article ; Online: LATS1/2 suppress NFκB and aberrant EMT initiation to permit pancreatic progenitor differentiation.

    Caitlin M Braitsch / D Berfin Azizoglu / Yadanar Htike / Haley R Barlow / Ulrike Schnell / Christopher P Chaney / Thomas J Carroll / Ben Z Stanger / Ondine Cleaver

    PLoS Biology, Vol 17, Iss 7, p e

    2019  Volume 3000382

    Abstract: The Hippo pathway directs cell differentiation during organogenesis, in part by restricting proliferation. How Hippo signaling maintains a proliferation-differentiation balance in developing tissues via distinct molecular targets is only beginning to be ... ...

    Abstract The Hippo pathway directs cell differentiation during organogenesis, in part by restricting proliferation. How Hippo signaling maintains a proliferation-differentiation balance in developing tissues via distinct molecular targets is only beginning to be understood. Our study makes the unexpected finding that Hippo suppresses nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) signaling in pancreatic progenitors to permit cell differentiation and epithelial morphogenesis. We find that pancreas-specific deletion of the large tumor suppressor kinases 1 and 2 (Lats1/2PanKO) from mouse progenitor epithelia results in failure to differentiate key pancreatic lineages: acinar, ductal, and endocrine. We carried out an unbiased transcriptome analysis to query differentiation defects in Lats1/2PanKO. This analysis revealed increased expression of NFκB activators, including the pantetheinase vanin1 (Vnn1). Using in vivo and ex vivo studies, we show that VNN1 activates a detrimental cascade of processes in Lats1/2PanKO epithelium, including (1) NFκB activation and (2) aberrant initiation of epithelial-mesenchymal transition (EMT), which together disrupt normal differentiation. We show that exogenous stimulation of VNN1 or NFκB can trigger this cascade in wild-type (WT) pancreatic progenitors. These findings reveal an unexpected requirement for active suppression of NFκB by LATS1/2 during pancreas development, which restrains a cell-autonomous deleterious transcriptional program and thereby allows epithelial differentiation.
    Keywords Biology (General) ; QH301-705.5
    Language English
    Publishing date 2019-07-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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