Publications by authors named "Barbara M Grüner"

18 Publications

  • Page 1 of 1

Statins affect cancer cell plasticity with distinct consequences for tumor progression and metastasis.

Cell Rep 2021 Nov;37(8):110056

Department of Medical Oncology, West German Cancer Center, University Hospital Essen at the University Duisburg-Essen, Duisburg, Germany; German Cancer Consortium (DKTK) partner site Essen, Essen, Germany. Electronic address:

Statins are among the most commonly prescribed drugs, and around every fourth person above the age of 40 is on statin medication. Therefore, it is of utmost clinical importance to understand the effect of statins on cancer cell plasticity and its consequences to not only patients with cancer but also patients who are on statins. Here, we find that statins induce a partial epithelial-to-mesenchymal transition (EMT) phenotype in cancer cells of solid tumors. Using a comprehensive STRING network analysis of transcriptome, proteome, and phosphoproteome data combined with multiple mechanistic in vitro and functional in vivo analyses, we demonstrate that statins reduce cellular plasticity by enforcing a mesenchymal-like cell state that increases metastatic seeding ability on one side but reduces the formation of (secondary) tumors on the other due to heterogeneous treatment responses. Taken together, we provide a thorough mechanistic overview of the consequences of statin use for each step of cancer development, progression, and metastasis.
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http://dx.doi.org/10.1016/j.celrep.2021.110056DOI Listing
November 2021

HER2 mediates clinical resistance to the KRAS inhibitor sotorasib, which is overcome by co-targeting SHP2.

Eur J Cancer 2021 Oct 26;159:16-23. Epub 2021 Oct 26.

Laboratory of Molecular Oncology, Department of Medical Oncology, West German Cancer Center, University Hospital Essen, Essen, Germany.

Introduction: Mutant RAS guanosine triphosphate hydrolases (GTPases) are key oncogenic drivers in many cancers. The KRAS variant has recently become targetable by a new drug class specifically locking KRAS in its inactive guanosine diphosphate (GDP)-bound state. Clinical activity was demonstrated in patients with advanced lung cancers harbouring KRAS mutations but was limited by the development of resistance.

Methods: A biopsy from progressing lung cancer of a patient treated with the KRAS inhibitor sotorasib was obtained, and the underlying resistance factors were analysed. Mechanistic studies were performed in vitro and in vivo to uncover strategies to overcome resistance to KRAS inhibition.

Results: We demonstrated acquisition of HER2 copy number gain and KRAS mutation retention in the post-progression biopsy. To explore HER2 gain as the relevant resistance mechanism, we generated KRAS lung cancer models overexpressing HER2. MAPK pathway signalling remained active despite KRAS inhibitor treatment. Combined pharmacological inhibition of KRAS and SHP2 synergistically overcame HER2-mediated resistance in vitro and in vivo.

Conclusions: These findings establish HER2 copy number gain as a clinically relevant mechanism of resistance to pharmacological KRAS inhibition that can be overcome by co-targeting SHP2.
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http://dx.doi.org/10.1016/j.ejca.2021.10.003DOI Listing
October 2021

Unraveling Tumor Heterogeneity by Using DNA Barcoding Technologies to Develop Personalized Treatment Strategies in Advanced-Stage PDAC.

Cancers (Basel) 2021 Aug 20;13(16). Epub 2021 Aug 20.

West German Cancer Center, Department of Medical Oncology, University Hospital Essen at the University Duisburg-Essen, 45147 Essen, Germany.

Tumor heterogeneity is a hallmark of many solid tumors, including pancreatic ductal adenocarcinoma (PDAC), and an inherent consequence of the clonal evolution of cancers. As such, it is considered the underlying concept of many characteristics of the disease, including the ability to metastasize, adapt to different microenvironments, and to develop therapy resistance. Undoubtedly, the high mortality of PDAC can be attributed to a high extent to these properties. Despite its apparent importance, studying tumor heterogeneity has been a challenging task, mainly due to its complexity and lack of appropriate methods. However, in recent years molecular DNA barcoding has emerged as a sophisticated tool that allows mapping of individual cells or subpopulations in a cell pool to study heterogeneity and thus devise new personalized treatment strategies. In this review, we provide an overview of genetic and non-genetic inter- and intra-tumor heterogeneity and its impact on (personalized) treatment strategies in PDAC and address how DNA barcoding technologies work and can be applied to study this clinically highly relevant question.
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http://dx.doi.org/10.3390/cancers13164187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8394487PMC
August 2021

Barcoding Technology for Multiplexed Analysis of Metastatic Ability In Vivo.

Methods Mol Biol 2021 ;2294:239-251

Department of Medical Oncology, West German Cancer Center, University Hospital Essen at the University of Duisburg-Essen, Essen, Germany.

DNA barcoding allows the quantitative, biomarker-free tracking of individual cell populations in mixed/heterogeneous cell pools. Here, we describe a multiplexed in vivo screening platform based on DNA barcoding technology to interrogate compound libraries for their effect on metastatic seeding in vivo. We apply next-generation sequencing (NGS) technology to quantitatively analyze high-throughput compound screening in mice. Up to 96 compounds and controls can be screened for their effect on metastatic ability in a single mouse.
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http://dx.doi.org/10.1007/978-1-0716-1350-4_17DOI Listing
June 2021

Altered Mitochondria Functionality Defines a Metastatic Cell State in Lung Cancer and Creates an Exploitable Vulnerability.

Cancer Res 2021 02 25;81(3):567-579. Epub 2020 Nov 25.

Department of Medical Oncology, West German Cancer Center, University Hospital Essen at the University of Duisburg-Essen, Essen, Germany.

Lung cancer is a prevalent and lethal cancer type that leads to more deaths than the next four major cancer types combined. Metastatic cancer spread is responsible for most cancer-related deaths but the cellular changes that enable cancer cells to leave the primary tumor and establish inoperable and lethal metastases remain poorly understood. To uncover genes that are specifically required to sustain metastasis survival or growth, we performed a genome-scale pooled lentiviral-shRNA library screen in cells that represent nonmetastatic and metastatic states of lung adenocarcinoma. Mitochondrial ribosome and mitochondria-associated genes were identified as top gene sets associated with metastasis-specific lethality. Metastasis-derived cell lines and metastases analyzed from an autochthonous lung cancer mouse model had lower mitochondrial membrane potential and reduced mitochondrial functionality than nonmetastatic primary tumors. Electron microscopy of metastases uncovered irregular mitochondria with bridging and loss of normal membrane structure. Consistent with these findings, compounds that inhibit mitochondrial translation or replication had a greater effect on the growth of metastasis-derived cells. Finally, mice with established tumors developed fewer metastases upon treatment with phenformin . These results suggest that the metastatic cell state in lung adenocarcinoma is associated with a specifically altered mitochondrial functionality that can be therapeutically exploited. SIGNIFICANCE: This study characterizes altered mitochondria functionality of the metastatic cell state in lung cancer and opens new avenues for metastasis-specific therapeutic targeting.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-1865DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8137518PMC
February 2021

Functional screening identifies aryl hydrocarbon receptor as suppressor of lung cancer metastasis.

Oncogenesis 2020 Nov 19;9(11):102. Epub 2020 Nov 19.

Laboratory of Molecular Oncology, Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany.

Lung cancer mortality largely results from metastasis. Despite curative surgery many patients with early-stage non-small cell lung cancer ultimately succumb to metastatic relapse. Current risk reduction strategies based on cytotoxic chemotherapy and radiation have only modest activity. Against this background, we functionally screened for novel metastasis modulators using a barcoded shRNA library and an orthotopic lung cancer model. We identified aryl hydrocarbon receptor (AHR), a sensor of xenobiotic chemicals and transcription factor, as suppressor of lung cancer metastasis. Knockdown of endogenous AHR induces epithelial-mesenchymal transition signatures, increases invasiveness of lung cancer cells in vitro and metastasis formation in vivo. Low intratumoral AHR expression associates with inferior outcome of patients with resected lung adenocarcinomas. Mechanistically, AHR triggers ATF4 signaling and represses matrix metalloproteinase activity, both counteracting metastatic programs. These findings link the xenobiotic defense system with control of lung cancer progression. AHR-regulated pathways are promising targets for innovative anti-metastatic strategies.
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http://dx.doi.org/10.1038/s41389-020-00286-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7677369PMC
November 2020

Axon-like protrusions promote small cell lung cancer migration and metastasis.

Elife 2019 12 13;8. Epub 2019 Dec 13.

Cancer Biology Program, Stanford University School of Medicine, Stanford, United States.

Metastasis is the main cause of death in cancer patients but remains a poorly understood process. Small cell lung cancer (SCLC) is one of the most lethal and most metastatic cancer types. SCLC cells normally express neuroendocrine and neuronal gene programs but accumulating evidence indicates that these cancer cells become relatively more neuronal and less neuroendocrine as they gain the ability to metastasize. Here we show that mouse and human SCLC cells in culture and in vivo can grow cellular protrusions that resemble axons. The formation of these protrusions is controlled by multiple neuronal factors implicated in axonogenesis, axon guidance, and neuroblast migration. Disruption of these axon-like protrusions impairs cell migration in culture and inhibits metastatic ability in vivo. The co-option of developmental neuronal programs is a novel molecular and cellular mechanism that contributes to the high metastatic ability of SCLC.
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http://dx.doi.org/10.7554/eLife.50616DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6940020PMC
December 2019

Hmga2 is dispensable for pancreatic cancer development, metastasis, and therapy resistance.

Sci Rep 2018 09 18;8(1):14008. Epub 2018 Sep 18.

Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany.

Expression of the chromatin-associated protein HMGA2 correlates with progression, metastasis and therapy resistance in pancreatic ductal adenocarcinoma (PDAC). Hmga2 has also been identified as a marker of a transient subpopulation of PDAC cells that has increased metastatic ability. Here, we characterize the requirement for Hmga2 during growth, dissemination, and metastasis of PDAC in vivo using conditional inactivation of Hmga2 in well-established autochthonous mouse models of PDAC. Overall survival, primary tumour burden, presence of disseminated tumour cells in the peritoneal cavity or circulating tumour cells in the blood, and presence and number of metastases were not significantly different between mice with Hmga2-wildtype or Hmga2-deficient tumours. Treatment of mice with Hmga2-wildtype and Hmga2-deficient tumours with gemcitabine did not uncover a significant impact of Hmga2-deficiency on gemcitabine sensitivity. Hmga1 and Hmga2 overlap in their expression in both human and murine PDAC, however knockdown of Hmga1 in Hmga2-deficient cancer cells also did not decrease metastatic ability. Thus, Hmga2 remains a prognostic marker which identifies a metastatic cancer cell state in primary PDAC, however Hmga2 has limited if any direct functional impact on PDAC progression and therapy resistance.
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http://dx.doi.org/10.1038/s41598-018-32159-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6143627PMC
September 2018

BLIMP1 Induces Transient Metastatic Heterogeneity in Pancreatic Cancer.

Cancer Discov 2017 10 8;7(10):1184-1199. Epub 2017 Aug 8.

Department of Genetics, Stanford University School of Medicine, Stanford, California.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most metastatic and deadly cancers. Despite the clinical significance of metastatic spread, our understanding of molecular mechanisms that drive PDAC metastatic ability remains limited. By generating a genetically engineered mouse model of human PDAC, we uncover a transient subpopulation of cancer cells with exceptionally high metastatic ability. Global gene expression profiling and functional analyses uncovered the transcription factor BLIMP1 as a driver of PDAC metastasis. The highly metastatic PDAC subpopulation is enriched for hypoxia-induced genes, and hypoxia-mediated induction of BLIMP1 contributes to the regulation of a subset of hypoxia-associated gene expression programs. These findings support a model in which upregulation of BLIMP1 links microenvironmental cues to a metastatic stem cell character. PDAC is an almost uniformly lethal cancer, largely due to its tendency for metastasis. We define a highly metastatic subpopulation of cancer cells, uncover a key transcriptional regulator of metastatic ability, and define hypoxia as an important factor within the tumor microenvironment that increases metastatic proclivity. .
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http://dx.doi.org/10.1158/2159-8290.CD-17-0250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5628145PMC
October 2017

Molecular definition of a metastatic lung cancer state reveals a targetable CD109-Janus kinase-Stat axis.

Nat Med 2017 Mar 13;23(3):291-300. Epub 2017 Feb 13.

Department of Genetics, Stanford University School of Medicine, Stanford, California, USA.

Lung cancer is the leading cause of cancer deaths worldwide, with the majority of mortality resulting from metastatic spread. However, the molecular mechanism by which cancer cells acquire the ability to disseminate from primary tumors, seed distant organs, and grow into tissue-destructive metastases remains incompletely understood. We combined tumor barcoding in a mouse model of human lung adenocarcinoma with unbiased genomic approaches to identify a transcriptional program that confers metastatic ability and predicts patient survival. Small-scale in vivo screening identified several genes, including Cd109, that encode novel pro-metastatic factors. We uncovered signaling mediated by Janus kinases (Jaks) and the transcription factor Stat3 as a critical, pharmacologically targetable effector of CD109-driven lung cancer metastasis. In summary, by coupling the systematic genomic analysis of purified cancer cells in distinct malignant states from mouse models with extensive human validation, we uncovered several key regulators of metastatic ability, including an actionable pro-metastatic CD109-Jak-Stat3 axis.
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http://dx.doi.org/10.1038/nm.4285DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6453542PMC
March 2017

An in vivo multiplexed small-molecule screening platform.

Nat Methods 2016 10 12;13(10):883-889. Epub 2016 Sep 12.

Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.

Phenotype-based small-molecule screening is a powerful method to identify molecules that regulate cellular functions. However, such screens are generally performed in vitro under conditions that do not necessarily model complex physiological conditions or disease states. Here, we use molecular cell barcoding to enable direct in vivo phenotypic screening of small-molecule libraries. The multiplexed nature of this approach allows rapid in vivo analysis of hundreds to thousands of compounds. Using this platform, we screened >700 covalent inhibitors directed toward hydrolases for their effect on pancreatic cancer metastatic seeding. We identified multiple hits and confirmed the relevant target of one compound as the lipase ABHD6. Pharmacological and genetic studies confirmed the role of this enzyme as a regulator of metastatic fitness. Our results highlight the applicability of this multiplexed screening platform for investigating complex processes in vivo.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5088491PMC
http://dx.doi.org/10.1038/nmeth.3992DOI Listing
October 2016

Nfib Promotes Metastasis through a Widespread Increase in Chromatin Accessibility.

Cell 2016 Jul 30;166(2):328-342. Epub 2016 Jun 30.

Cancer Biology Program, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA; Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address:

Metastases are the main cause of cancer deaths, but the mechanisms underlying metastatic progression remain poorly understood. We isolated pure populations of cancer cells from primary tumors and metastases from a genetically engineered mouse model of human small cell lung cancer (SCLC) to investigate the mechanisms that drive the metastatic spread of this lethal cancer. Genome-wide characterization of chromatin accessibility revealed the opening of large numbers of distal regulatory elements across the genome during metastatic progression. These changes correlate with copy number amplification of the Nfib locus, and differentially accessible sites were highly enriched for Nfib transcription factor binding sites. Nfib is necessary and sufficient to increase chromatin accessibility at a large subset of the intergenic regions. Nfib promotes pro-metastatic neuronal gene expression programs and drives the metastatic ability of SCLC cells. The identification of widespread chromatin changes during SCLC progression reveals an unexpected global reprogramming during metastatic progression.
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http://dx.doi.org/10.1016/j.cell.2016.05.052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5004630PMC
July 2016

Modeling Therapy Response and Spatial Tissue Distribution of Erlotinib in Pancreatic Cancer.

Mol Cancer Ther 2016 05 28;15(5):1145-52. Epub 2016 Jan 28.

2. Medizinische Klinik, Technische Universität München, Munich, Germany. German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany. Division of Solid Tumor Translational Oncology, German Cancer Consortium (DKTK) Partner Site Essen, West German Cancer Center, University Hospital Essen, Essen, Germany.

Pancreatic ductal adenocarcinoma (PDAC) is likely the most aggressive and therapy-resistant of all cancers. The aim of this study was to investigate the emerging technology of matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI IMS) as a powerful tool to study drug delivery and spatial tissue distribution in PDAC. We utilized an established genetically engineered mouse model of spontaneous PDAC to examine the distribution of the small-molecule inhibitor erlotinib in healthy pancreas and PDAC. MALDI IMS was utilized on sections of single-dose or long-term-treated mice to measure drug tissue distribution. Histologic and statistical analyses were performed to correlate morphology, drug distribution, and survival. We found that erlotinib levels were significantly lower in PDAC compared with healthy tissue (P = 0.0078). Survival of long-term-treated mice did not correlate with overall levels of erlotinib or with overall histologic tumor grade but did correlate both with the percentage of atypical glands in the cancer (P = 0.021, rs = 0.59) and the level of erlotinib in those atypical glands (P = 0.019, rs = 0.60). The results of this pilot study present MALDI IMS as a reliable technology to study drug delivery and spatial distribution of compounds in a preclinical setting and support drug imaging-based translational approaches. Mol Cancer Ther; 15(5); 1145-52. ©2016 AACR.
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http://dx.doi.org/10.1158/1535-7163.MCT-15-0165DOI Listing
May 2016

Pancreatic cancer modeling using retrograde viral vector delivery and in vivo CRISPR/Cas9-mediated somatic genome editing.

Genes Dev 2015 Jul 15;29(14):1576-85. Epub 2015 Jul 15.

Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA; Cancer Biology Program, Stanford University School of Medicine, Stanford, California 94305, USA; Stanford Cancer Institute, Stanford University School of Medicine, Stanford, California 94305, USA; Department of Pathology, Stanford University School of Medicine, Stanford, California 94305, USA.

Pancreatic ductal adenocarcinoma (PDAC) is a genomically diverse, prevalent, and almost invariably fatal malignancy. Although conventional genetically engineered mouse models of human PDAC have been instrumental in understanding pancreatic cancer development, these models are much too labor-intensive, expensive, and slow to perform the extensive molecular analyses needed to adequately understand this disease. Here we demonstrate that retrograde pancreatic ductal injection of either adenoviral-Cre or lentiviral-Cre vectors allows titratable initiation of pancreatic neoplasias that progress into invasive and metastatic PDAC. To enable in vivo CRISPR/Cas9-mediated gene inactivation in the pancreas, we generated a Cre-regulated Cas9 allele and lentiviral vectors that express Cre and a single-guide RNA. CRISPR-mediated targeting of Lkb1 in combination with oncogenic Kras expression led to selection for inactivating genomic alterations, absence of Lkb1 protein, and rapid tumor growth that phenocopied Cre-mediated genetic deletion of Lkb1. This method will transform our ability to rapidly interrogate gene function during the development of this recalcitrant cancer.
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http://dx.doi.org/10.1101/gad.264861.115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4526740PMC
July 2015

EGF receptor is required for KRAS-induced pancreatic tumorigenesis.

Cancer Cell 2012 Sep;22(3):304-17

Department of Pharmacological Sciences, Stony Brook University, Stony Brook, NY 11794, USA.

Initiation of pancreatic ductal adenocarcinoma (PDA) is definitively linked to activating mutations in the KRAS oncogene. However, PDA mouse models show that mutant Kras expression early in development gives rise to a normal pancreas, with tumors forming only after a long latency or pancreatitis induction. Here, we show that oncogenic KRAS upregulates endogenous EGFR expression and activation, the latter being dependent on the EGFR ligand sheddase, ADAM17. Genetic ablation or pharmacological inhibition of EGFR or ADAM17 effectively eliminates KRAS-driven tumorigenesis in vivo. Without EGFR activity, active RAS levels are not sufficient to induce robust MEK/ERK activity, a requirement for epithelial transformation.
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http://dx.doi.org/10.1016/j.ccr.2012.07.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3443395PMC
September 2012

MALDI imaging mass spectrometry for in situ proteomic analysis of preneoplastic lesions in pancreatic cancer.

PLoS One 2012 26;7(6):e39424. Epub 2012 Jun 26.

II Medizinische Klinik, Technische Universität München, Munich, Germany.

The identification of new biomarkers for preneoplastic pancreatic lesions (PanINs, IPMNs) and early pancreatic ductal adenocarcinoma (PDAC) is crucial due to the diseases high mortality rate upon late detection. To address this task we used the novel technique of matrix-assisted laser desorption/ionization (MALDI) imaging mass spectrometry (IMS) on genetically engineered mouse models (GEM) of pancreatic cancer. Various GEM were analyzed with MALDI IMS to investigate the peptide/protein-expression pattern of precursor lesions in comparison to normal pancreas and PDAC with cellular resolution. Statistical analysis revealed several discriminative m/z-species between normal and diseased tissue. Intraepithelial neoplasia (PanIN) and intraductal papillary mucinous neoplasm (IPMN) could be distinguished from normal pancreatic tissue and PDAC by 26 significant m/z-species. Among these m/z-species, we identified Albumin and Thymosin-beta 4 by liquid chromatography and tandem mass spectrometry (LC-MS/MS), which were further validated by immunohistochemistry, western blot, quantitative RT-PCR and ELISA in both murine and human tissue. Thymosin-beta 4 was found significantly increased in sera of mice with PanIN lesions. Upregulated PanIN expression of Albumin was accompanied by increased expression of liver-restricted genes suggesting a hepatic transdifferentiation program of preneoplastic cells. In conclusion we show that GEM of endogenous PDAC are a suitable model system for MALDI-IMS and subsequent LC-MS/MS analysis, allowing in situ analysis of small precursor lesions and identification of differentially expressed peptides and proteins.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0039424PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3383687PMC
March 2013

Identification of epidermal Pdx1 expression discloses different roles of Notch1 and Notch2 in murine Kras(G12D)-induced skin carcinogenesis in vivo.

PLoS One 2010 Oct 22;5(10):e13578. Epub 2010 Oct 22.

2nd Department of Internal Medicine, Klinikum Rechts der Isar University Hospital, Technical University of Munich, Munich, Germany.

Background: The Ras and Notch signaling pathways are frequently activated during development to control many diverse cellular processes and are often dysregulated during tumorigenesis. To study the role of Notch and oncogenic Kras signaling in a progenitor cell population, Pdx1-Cre mice were utilized to generate conditional oncogenic Kras(G12D) mice with ablation of Notch1 and/or Notch2.

Methodology/principal Findings: Surprisingly, mice with activated Kras(G12D) and Notch1 but not Notch2 ablation developed skin papillomas progressing to squamous cell carcinoma providing evidence for Pdx1 expression in the skin. Immunostaining and lineage tracing experiments indicate that PDX1 is present predominantly in the suprabasal layers of the epidermis and rarely in the basal layer. Further analysis of keratinocytes in vitro revealed differentiation-dependent expression of PDX1 in terminally differentiated keratinocytes. PDX1 expression was also increased during wound healing. Further analysis revealed that loss of Notch1 but not Notch2 is critical for skin tumor development. Reasons for this include distinct Notch expression with Notch1 in all layers and Notch2 in the suprabasal layer as well as distinctive p21 and β-catenin signaling inhibition capabilities.

Conclusions/significance: Our results provide strong evidence for epidermal expression of Pdx1 as of yet not identified function. In addition, this finding may be relevant for research using Pdx1-Cre transgenic strains. Additionally, our study confirms distinctive expression and functions of Notch1 and Notch2 in the skin supporting the importance of careful dissection of the contribution of individual Notch receptors.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0013578PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2962652PMC
October 2010
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