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      CAF hierarchy driven by pancreatic cancer cell p53-status creates a pro-metastatic and chemoresistant environment via perlecan

      research-article
      1 , 2 , 3 , 1 , 2 , 1 , 2 , 1 , 2 , 1 , 2 , 1 , 2 , 1 , 2 , 1 , 2 , 1 , 2 , 1 , 2 , 4 , 1 , 2 , 5 , 1 , 2 , 6 , 1 , 1 , 2 , 1 , 1 , 2 , 7 , Australian Pancreatic Genome Initiative (APGI), 6 , 8 , 9 , 10 , 11 , 1 , 2 , 12 , 1 , 2 , 13 , 14 , 4 , 1 , 15 , 16 , 17 , 5 , 1 , 2 , 18 , 1 , 2 , 5 , 1 , 2 , , 1 , 2 ,
      Nature Communications
      Nature Publishing Group UK
      Cancer, Cancer microenvironment, Cell biology

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          Abstract

          Heterogeneous subtypes of cancer-associated fibroblasts (CAFs) coexist within pancreatic cancer tissues and can both promote and restrain disease progression. Here, we interrogate how cancer cells harboring distinct alterations in p53 manipulate CAFs. We reveal the existence of a p53-driven hierarchy, where cancer cells with a gain-of-function (GOF) mutant p53 educate a dominant population of CAFs that establish a pro-metastatic environment for GOF and null p53 cancer cells alike. We also demonstrate that CAFs educated by null p53 cancer cells may be reprogrammed by either GOF mutant p53 cells or their CAFs. We identify perlecan as a key component of this pro-metastatic environment. Using intravital imaging, we observe that these dominant CAFs delay cancer cell response to chemotherapy. Lastly, we reveal that depleting perlecan in the stroma combined with chemotherapy prolongs mouse survival, supporting it as a potential target for anti-stromal therapies in pancreatic cancer.

          Abstract

          Subtypes of cancer associated fibroblasts can both promote and suppress tumorigenesis. Here, the authors investigate how p53 status in pancreatic cancer cells affects their interaction with cancer associated fibroblasts, and report perlecan as a mediator of the pro-metastatic environment.

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          Most cited references47

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          Virtual microdissection identifies distinct tumor- and stroma-specific subtypes of pancreatic ductal adenocarcinoma

          Pancreatic ductal adenocarcinoma (PDAC) remains a lethal disease with a 5-year survival of 4%. A key hallmark of PDAC is extensive stromal involvement, which makes capturing precise tumor-specific molecular information difficult. Here, we have overcome this problem by applying blind source separation to a diverse collection of PDAC gene expression microarray data, which includes primary, metastatic, and normal samples. By digitally separating tumor, stroma, and normal gene expression, we have identified and validated two tumor-specific subtypes including a “basal-like” subtype which has worse outcome, and is molecularly similar to basal tumors in bladder and breast cancer. Furthermore, we define “normal” and “activated” stromal subtypes which are independently prognostic. Our results provide new insight into the molecular composition of PDAC which may be used to tailor therapies or provide decision support in a clinical setting where the choice and timing of therapies is critical.
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            • Record: found
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            Cancer. p53, guardian of the genome.

            D P Lane (1992)
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              Mutant p53 in Cancer: New Functions and Therapeutic Opportunities

              Many different types of cancer show a high incidence of TP53 mutations, leading to the expression of mutant p53 proteins. There is growing evidence that these mutant p53s have both lost wild-type p53 tumor suppressor activity and gained functions that help to contribute to malignant progression. Understanding the functions of mutant p53 will help in the development of new therapeutic approaches that may be useful in a broad range of cancer types.
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                Author and article information

                Contributors
                t.cox@garvan.org.au
                p.timpson@garvan.org.au
                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group UK (London )
                2041-1723
                12 August 2019
                12 August 2019
                2019
                : 10
                : 3637
                Affiliations
                [1 ]ISNI 0000 0000 9983 6924, GRID grid.415306.5, The Garvan Institute of Medical Research & The Kinghorn Cancer Centre, ; Sydney, NSW 2010 Australia
                [2 ]ISNI 0000 0004 4902 0432, GRID grid.1005.4, St Vincent’s Clinical School, Faculty of Medicine, , University of New South Wales Sydney, ; Sydney, NSW 2010 Australia
                [3 ]GRID grid.430814.a, Molecular Pathology department, , the Netherlands Cancer Institute, ; Amsterdam, 1066CX the Netherlands
                [4 ]ISNI 0000 0004 4902 0432, GRID grid.1005.4, Graduate school of Biomedical Engineering, , University of New South Wales Sydney, ; Sydney, NSW 2052 Australia
                [5 ]ISNI 0000 0000 8821 5196, GRID grid.23636.32, Cancer Research UK Beatson Institute, ; Glasgow Scotland, G61 BD UK
                [6 ]ISNI 0000 0001 2342 0938, GRID grid.1018.8, Department of Physiology, Anatomy and Microbiology, School of Life Sciences, , La Trobe University, ; Bundoora, VIC 3086 Australia
                [7 ]ISNI 000000041936877X, GRID grid.5386.8, Department of Biomedical Sciences, College of Veterinary Medicine, , Cornell University, ; Ithaca, NY 14853 USA
                [8 ]ISNI 0000 0001 2107 4242, GRID grid.266100.3, Department of Bioengineering, Institute of Engineering in Medicine, , University of California, ; San Diego, CA 92121 USA
                [9 ]ISNI 0000 0004 1936 834X, GRID grid.1013.3, Children’s Medical Research Institute, , University of Sydney, ; Sydney, NSW 2006 Australia
                [10 ]ISNI 0000 0004 1936 7830, GRID grid.29980.3a, Department of Pathology, Dunedin School of Medicine, , University of Otago, ; Dunedin, 9054 New Zealand
                [11 ]ISNI 0000 0004 1936 7830, GRID grid.29980.3a, Maurice Wilkins Centre, , University of Otago, ; Dunedin, 9054 New Zealand
                [12 ]ISNI 0000 0004 4902 0432, GRID grid.1005.4, Biomedical imaging facility, Lowy Cancer Research Centre, , University of New South Wales, ; Sydney, NSW Australia
                [13 ]ISNI 0000 0004 4902 0432, GRID grid.1005.4, Pancreatic Cancer Translational Research Group, Lowy Cancer Research Centre, School of Medical Sciences, , University of New South Wales, ; Sydney, NSW 2052 Australia
                [14 ]ISNI 0000 0004 4902 0432, GRID grid.1005.4, Australian Centre for Nanomedicine, , University of New South Wales, ; Sydney, NSW 2052 Australia
                [15 ]ISNI 0000 0004 1936 834X, GRID grid.1013.3, Sydney Medical School, , University of Sydney, ; Sydney, NSW 2006 Australia
                [16 ]ISNI 0000 0004 0587 9093, GRID grid.412703.3, NSW Health Pathology, Department of Anatomical Pathology, , Royal North Shore Hospital, St Leonards, ; Sydney, NSW 2065 Australia
                [17 ]ISNI 0000 0004 1936 834X, GRID grid.1013.3, Cancer Diagnosis and Pathology Research Group, , Kolling Institute of Medical Research, ; St Leonards, NSW 2065 Australia
                [18 ]ISNI 0000 0004 1936 834X, GRID grid.1013.3, Schools of Life and Environmental Sciences, the Charles Perkin Centre, , the University of Sydney, ; Sydney, NSW 2006 Australia
                [19 ]ISNI 0000 0000 9983 6924, GRID grid.415306.5, The Kinghorn Cancer Centre, , Garvan Institute of Medical Research, ; 370 Victoria Street, Darlinghurst, Sydney, NSW 2010 Australia
                [20 ]ISNI 0000 0000 9781 7439, GRID grid.417154.2, Wollongong Hospital, Illawarra and Shoalhaven Local Health District, ; Loftus Street, Wollongong, NSW 2500 Australia
                [21 ]ISNI 0000 0004 0587 9093, GRID grid.412703.3, Royal North Shore Hospital, ; Westbourne Street, St Leonards, NSW 2065 Australia
                [22 ]ISNI 0000 0001 2294 1395, GRID grid.1049.c, QIMR Berghofer Medical Research Institute, ; 300 Herston Rd, Herston, QLD 4006 Australia
                [23 ]ISNI 0000 0001 2179 088X, GRID grid.1008.9, University of Melbourne, Centre for Cancer Research, Victorian Comprehensive Cancer Centre, ; 305 Grattan Street, Melbourne, VIC 3000 Australia
                [24 ]ISNI 0000 0000 9320 7537, GRID grid.1003.2, Institute for Molecular Bioscience, , University of QLD, ; St Lucia, QLD 4072 Australia
                [25 ]Bankstown Hospital, Eldridge Road, Bankstown, NSW 2200 Australia
                [26 ]ISNI 0000 0004 0527 9653, GRID grid.415994.4, Liverpool Hospital, ; Elizabeth Street, Liverpool, NSW 2170 Australia
                [27 ]ISNI 0000 0000 9119 2677, GRID grid.437825.f, St Vincent’s Hospital, ; 390 Victoria Street, Darlinghurst, N W 2010 Australia
                [28 ]ISNI 0000 0001 0180 6477, GRID grid.413252.3, Westmead Hospital, ; Hawkesbury and Darcy Roads, Westmead, NSW 2145 Australia
                [29 ]ISNI 0000 0004 0385 0051, GRID grid.413249.9, Royal Prince Alfred Hospital, ; Missenden Road, Camperdown, NSW 2050 Australia
                [30 ]GRID grid.415193.b, Prince of Wales Hospital, ; Barker Street, Randwick, NSW 2031 Australia
                [31 ]ISNI 0000 0004 0402 6638, GRID grid.415051.4, Fremantle Hospital, ; Alma Street, Fremantle, WA 6959 Australia
                [32 ]ISNI 0000 0004 0437 5942, GRID grid.3521.5, Sir Charles Gairdner Hospital, ; Hospital Avenue, Nedlands, WA 6009 Australia
                [33 ]St John of God Healthcare, 12 Salvado Road, Subiaco, WA 6008 Australia
                [34 ]ISNI 0000 0004 0367 1221, GRID grid.416075.1, Royal Adelaide Hospital, North Terrace, ; Adelaide, SA 5000 Australia
                [35 ]ISNI 0000 0000 9685 0624, GRID grid.414925.f, Flinders Medical Centre, Flinders Drive, ; Bedford Park, SA 5042 Australia
                [36 ]Envoi Pathology, 1/49 Butterfield Street, Herston, QLD 4006 Australia
                [37 ]Princess Alexandria Hospital, Cornwall Street & Ipswich Road, Woolloongabba, QLD 4102 Australia
                [38 ]ISNI 0000 0001 0162 7225, GRID grid.414094.c, Austin Hospital, ; 145 Studley Road, Heidelberg, VIC 3084 Australia
                [39 ]ISNI 0000 0001 2171 9311, GRID grid.21107.35, Johns Hopkins Medical Institute, ; 600 North Wolfe Street, Baltimore, MD 21287 USA
                [40 ]ISNI 0000 0004 1763 1124, GRID grid.5611.3, ARC-NET Center for Applied Research on Cancer, , University of Verona, ; Via dell’Artigliere, 19, Verona, 37129 Province of Verona Italy
                [41 ]ISNI 0000 0001 2193 314X, GRID grid.8756.c, Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, , University of Glasgow, Garscube Estate, ; Switchback Road, Bearsden, Glasgow, Scotland, G61 1BD UK
                Author information
                http://orcid.org/0000-0003-4210-9613
                http://orcid.org/0000-0001-7075-8448
                http://orcid.org/0000-0002-9514-7501
                http://orcid.org/0000-0002-3736-7725
                http://orcid.org/0000-0002-5253-7147
                http://orcid.org/0000-0001-5078-6687
                http://orcid.org/0000-0003-2160-1625
                http://orcid.org/0000-0003-0265-326X
                http://orcid.org/0000-0002-7313-3977
                http://orcid.org/0000-0001-9540-3010
                http://orcid.org/0000-0001-5766-9141
                http://orcid.org/0000-0001-9294-1745
                Article
                10968
                10.1038/s41467-019-10968-6
                6691013
                31406163
                4188f172-1a08-44c3-8bc6-c079a39a6dc1
                © The Author(s) 2019

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 21 June 2018
                : 11 June 2019
                Funding
                Funded by: FundRef https://doi.org/10.13039/501100000854, Human Frontier Science Program (HFSP);
                Funded by: FundRef https://doi.org/10.13039/501100000925, Department of Health | National Health and Medical Research Council (NHMRC);
                Funded by: FundRef https://doi.org/10.13039/501100001102, Cancer Council NSW (Cancer Council New South Wales);
                Categories
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                Custom metadata
                © The Author(s) 2019

                Uncategorized
                cancer,cancer microenvironment,cell biology
                Uncategorized
                cancer, cancer microenvironment, cell biology

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