44
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: not found

      CYP3A5 mediates basal and acquired therapy resistance in different subtypes of pancreatic ductal adenocarcinoma

      research-article

      Read this article at

      ScienceOpenPublisherPMC
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Although subtypes of pancreatic ductal adenocarcinoma (PDAC) were described, this malignancy is clinically still treated as a single disease. Here, we present patient-derived models representing the full spectrum of previously identified quasi-mesenchymal (QM-PDA), classical and exocrine-like PDAC subtypes, and identify two markers—HNF1A and KRT81—that enable stratification of tumors into different subtypes by immunohistochemistry. Individuals bearing tumors of these subtypes show significant differences in overall survival and their tumors differ in drug sensitivity, with the exocrine-like subtype being resistant to tyrosine kinase inhibitors and paclitaxel. Cytochrome P450 3A5 (CYP3A5) metabolizes these compounds in tumors of the exocrine-like subtype, and pharmacological or shRNA-mediated CYP3A5 inhibition sensitizes tumor cells to these drugs. Whereas hepatocyte nuclear factor 4 alpha (HNF4A) controls basal expression of CYP3A5, drug-induced CYP3A5 upregulation is mediated by the nuclear receptor NR1I2. CYP3A5 also contributes to acquired drug resistance in QM-PDA and classical PDAC, and is highly expressed in several additional malignancies. These findings designate CYP3A5 as predictor of therapy response and as a tumor cell-autonomous detoxification mechanism that must be overcome to prevent drug resistance.

          Related collections

          Most cited references50

          • Record: found
          • Abstract: found
          • Article: not found

          Variance stabilization applied to microarray data calibration and to the quantification of differential expression.

          We introduce a statistical model for microarray gene expression data that comprises data calibration, the quantification of differential expression, and the quantification of measurement error. In particular, we derive a transformation h for intensity measurements, and a difference statistic Deltah whose variance is approximately constant along the whole intensity range. This forms a basis for statistical inference from microarray data, and provides a rational data pre-processing strategy for multivariate analyses. For the transformation h, the parametric form h(x)=arsinh(a+bx) is derived from a model of the variance-versus-mean dependence for microarray intensity data, using the method of variance stabilizing transformations. For large intensities, h coincides with the logarithmic transformation, and Deltah with the log-ratio. The parameters of h together with those of the calibration between experiments are estimated with a robust variant of maximum-likelihood estimation. We demonstrate our approach on data sets from different experimental platforms, including two-colour cDNA arrays and a series of Affymetrix oligonucleotide arrays.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Recent progress in pancreatic cancer.

            Pancreatic cancer is currently one of the deadliest of the solid malignancies. However, surgery to resect neoplasms of the pancreas is safer and less invasive than ever, novel drug combinations have been shown to improve survival, advances in radiation therapy have resulted in less toxicity, and enormous strides have been made in the understanding of the fundamental genetics of pancreatic cancer. These advances provide hope but they also increase the complexity of caring for patients. It is clear that multidisciplinary care that provides comprehensive and coordinated evaluation and treatment is the most effective way to manage patients with pancreatic cancer. Copyright © 2013 American Cancer Society, Inc.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Single-cell cloning of colon cancer stem cells reveals a multi-lineage differentiation capacity.

              Colon carcinoma is one of the leading causes of death from cancer and is characterized by a heterogenic pool of cells with distinct differentiation patterns. Recently, it was reported that a population of undifferentiated cells from a primary tumor, so-called cancer stem cells (CSC), can reconstitute the original tumor on xenotransplantation. Here, we show that spheroid cultures of these colon CSCs contain expression of CD133, CD166, CD44, CD29, CD24, Lgr5, and nuclear beta-catenin, which have all been suggested to mark the (cancer) stem cell population. More importantly, by using these spheroid cultures or freshly isolated tumor cells from multiple colon carcinomas, we now provide compelling evidence to indicate that the capacity to propagate a tumor with all differentiated progeny resides in a single CSC. Single-cell-cloned CSCs can form an adenocarcinoma on xenotransplantation but do not generate the stroma within these tumors. Moreover, they can self-renew and are capable of multilineage differentiation. Further analysis indicated that the lineage decision is dictated by phosphoinositide 3-kinase (PI3K) signaling in CSCs. These data support the hypothesis that tumor hierarchy can be traced back to a single CSC that contains multilineage differentiation capacity, and provides clues to the regulation of differentiation in colon cancers in vivo.
                Bookmark

                Author and article information

                Journal
                9502015
                8791
                Nat Med
                Nat. Med.
                Nature medicine
                1078-8956
                1546-170X
                19 February 2016
                08 February 2016
                March 2016
                01 September 2016
                : 22
                : 3
                : 278-287
                Affiliations
                [1 ]Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Heidelberg, Germany
                [2 ]Divison of Stem Cells and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany
                [3 ]Department of Pathology, University of Heidelberg, Heidelberg, Germany
                [4 ]National Center for Tumor Diseases (NCT), Heidelberg, Germany
                [5 ]European Molecular Biology Laboratory, Genome Biology Unit, Heidelberg, Germany
                [6 ]Heidelberg Pharma GmbH, Ladenburg, Germany
                [7 ]Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany
                [8 ]Division of Biostatistics, German Cancer Research Center (DKFZ), Heidelberg, Germany
                [9 ]Department of General, Visceral and Transplantation Surgery, Charité-Universitätsmedizin Berlin, Berlin, Germany
                [10 ]Institute of Pathology, Charité-Universitätsmedizin Berlin, Berlin, Germany
                [11 ]Institute of Pharmacy and Molecular Biotechnology, Bioquant, University of Heidelberg, Heidelberg, Germany
                [12 ]Heidelberg Center for Personalized Oncology (DKFZ-HIPO), German Cancer Research Center (DKFZ), Heidelberg, Germany
                [13 ]Department of General and Visceral Surgery, University Hospital Heidelberg, Heidelberg, Germany
                [14 ]German Cancer Consortium (DKTK), Heidelberg, Germany
                Author notes
                Correspondence should be addressed to A.T. ( a.trumpp@ 123456dkfz.de ) or M.R.S. ( martin.sprick@ 123456hi-stem.de )

                Author Contributions

                E.N. and C.E. established, conducted and analyzed the experiments; A.S., A.M. and W.W. performed immunohistological analyses of all tissue specimens presented and performed respective data analyses; E.E. carried out immunofluorescence stainings and analyses on publicly available datasets; B.K., W.N. and C.R. performed RNA expression analyses on the PDAC validation cohort; C.K., V.V., J.E., F.Z., O.E., M.S. and R.E. provided technical and experimental support; C.L. and M.K. conducted and analyzed LC-MS/MS experiments; X.J. and A.K-S. performed activity area calculations; P.N., M.B. and B.S. provided PDAC tissue microarray characterization; N.G., T.H., O.S., J.W. and M.W.B. provided samples of individuals with PDAC; A.T. and M.R.S. supervised the project; E.N., C.E., A.T. and M.R.S. developed the concept, designed experimental studies, analyzed the data and wrote the manuscript.

                [15]

                Present address: Department of Pathology, Center for Integrated Diagnostics (CID), Massachusetts General Hospital, Boston, USA

                [16]

                Present address: Institute of Pathology, Technical University Munich (TUM), Munich, Germany

                [17]

                Present address: Sandoz Biopharmaceuticals, Oberhaching, Germany

                [18]

                Present address: Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University, Munich, Germany

                [19]

                These authors contributed equally to this work.

                [20]

                These authors contributed equally to this work.

                Article
                EMS66580
                10.1038/nm.4038
                4780258
                26855150
                9cfb008b-efee-44f1-9e3f-b76ead20a330

                Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms

                History
                Categories
                Article

                Medicine
                Medicine

                Comments

                Comment on this article