Temporally resolved proteomics identifies nidogen-2 as a cotarget in pancreatic cancer that modulates fibrosis and therapy response.

Autor: Pereira BA; Cancer Ecosystems Program, Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia.; School of Clinical Medicine, Faculty of Medicine, University of New South Wales (UNSW) Sydney, Kensington, New South Wales, Australia., Ritchie S; Cancer Ecosystems Program, Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia.; School of Clinical Medicine, Faculty of Medicine, University of New South Wales (UNSW) Sydney, Kensington, New South Wales, Australia., Chambers CR; Cancer Ecosystems Program, Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia.; School of Clinical Medicine, Faculty of Medicine, University of New South Wales (UNSW) Sydney, Kensington, New South Wales, Australia., Gordon KA; Cancer Ecosystems Program, Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia.; School of Clinical Medicine, Faculty of Medicine, University of New South Wales (UNSW) Sydney, Kensington, New South Wales, Australia., Magenau A; Cancer Ecosystems Program, Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia.; School of Clinical Medicine, Faculty of Medicine, University of New South Wales (UNSW) Sydney, Kensington, New South Wales, Australia., Murphy KJ; Cancer Ecosystems Program, Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia.; School of Clinical Medicine, Faculty of Medicine, University of New South Wales (UNSW) Sydney, Kensington, New South Wales, Australia., Nobis M; Cancer Ecosystems Program, Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia.; School of Clinical Medicine, Faculty of Medicine, University of New South Wales (UNSW) Sydney, Kensington, New South Wales, Australia.; Intravital Imaging Expertise Center, VIB Center for Cancer Biology, VIB, Leuven, Belgium., Tyma VM; Cancer Ecosystems Program, Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia., Liew YF; Cancer Ecosystems Program, Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia., Lucas MC; Cancer Ecosystems Program, Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia.; School of Clinical Medicine, Faculty of Medicine, University of New South Wales (UNSW) Sydney, Kensington, New South Wales, Australia.; Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology, Barcelona, Spain.; Universitat Pompeu Fabra (UPF), Barcelona, Spain., Naeini MM; School of Clinical Medicine, Faculty of Medicine, University of New South Wales (UNSW) Sydney, Kensington, New South Wales, Australia.; Genomics and Inherited Disease Program, Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia., Barkauskas DS; Cancer Ecosystems Program, Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia.; ACRF INCITe Intravital Imaging Centre, Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia., Chacon-Fajardo D; School of Clinical Medicine, Faculty of Medicine, University of New South Wales (UNSW) Sydney, Kensington, New South Wales, Australia.; Translational Oncology Program, Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia., Howell AE; Cancer Ecosystems Program, Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia., Parker AL; Cancer Ecosystems Program, Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia.; School of Clinical Medicine, Faculty of Medicine, University of New South Wales (UNSW) Sydney, Kensington, New South Wales, Australia., Warren SC; Cancer Ecosystems Program, Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia.; School of Clinical Medicine, Faculty of Medicine, University of New South Wales (UNSW) Sydney, Kensington, New South Wales, Australia., Reed DA; Cancer Ecosystems Program, Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia.; School of Clinical Medicine, Faculty of Medicine, University of New South Wales (UNSW) Sydney, Kensington, New South Wales, Australia., Lee V; Cancer Ecosystems Program, Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia., Metcalf XL; Cancer Ecosystems Program, Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia., Lee YK; Cancer Ecosystems Program, Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia., O'Regan LP; Cancer Ecosystems Program, Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia., Zhu J; Cancer Ecosystems Program, Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia.; School of Clinical Medicine, Faculty of Medicine, University of New South Wales (UNSW) Sydney, Kensington, New South Wales, Australia., Trpceski M; Cancer Ecosystems Program, Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia.; School of Clinical Medicine, Faculty of Medicine, University of New South Wales (UNSW) Sydney, Kensington, New South Wales, Australia., Fontaine ARM; Cancer Ecosystems Program, Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia.; School of Clinical Medicine, Faculty of Medicine, University of New South Wales (UNSW) Sydney, Kensington, New South Wales, Australia.; ACRF INCITe Intravital Imaging Centre, Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia., Stoehr J; Cancer Ecosystems Program, Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia., Rouet R; School of Clinical Medicine, Faculty of Medicine, University of New South Wales (UNSW) Sydney, Kensington, New South Wales, Australia.; Immune Biotherapies Program, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia., Lin X; Data Science Platform, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia., Chitty JL; Cancer Ecosystems Program, Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia.; School of Clinical Medicine, Faculty of Medicine, University of New South Wales (UNSW) Sydney, Kensington, New South Wales, Australia., Porazinski S; School of Clinical Medicine, Faculty of Medicine, University of New South Wales (UNSW) Sydney, Kensington, New South Wales, Australia.; Translational Oncology Program, Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia., Wu SZ; Cancer Ecosystems Program, Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia.; School of Clinical Medicine, Faculty of Medicine, University of New South Wales (UNSW) Sydney, Kensington, New South Wales, Australia.; Genentech Inc., South San Francisco, CA, USA., Filipe EC; Cancer Ecosystems Program, Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia.; School of Clinical Medicine, Faculty of Medicine, University of New South Wales (UNSW) Sydney, Kensington, New South Wales, Australia., Cadell AL; School of Clinical Medicine, Faculty of Medicine, University of New South Wales (UNSW) Sydney, Kensington, New South Wales, Australia.; Translational Oncology Program, Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia., Holliday H; Cancer Ecosystems Program, Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia.; School of Clinical Medicine, Faculty of Medicine, University of New South Wales (UNSW) Sydney, Kensington, New South Wales, Australia.; Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney, Kensington, New South Wales, Australia., Yang J; Cancer Ecosystems Program, Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia.; School of Clinical Medicine, Faculty of Medicine, University of New South Wales (UNSW) Sydney, Kensington, New South Wales, Australia., Papanicolaou M; Cancer Ecosystems Program, Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia.; School of Clinical Medicine, Faculty of Medicine, University of New South Wales (UNSW) Sydney, Kensington, New South Wales, Australia., Lyons RJ; Cancer Ecosystems Program, Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia., Zaratzian A; Histopathology Platform, Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia., Tayao M; Histopathology Platform, Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia., Da Silva A; Histopathology Platform, Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia., Vennin C; Cancer Ecosystems Program, Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia.; School of Clinical Medicine, Faculty of Medicine, University of New South Wales (UNSW) Sydney, Kensington, New South Wales, Australia.; Division of Molecular Pathology, Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, Netherlands.; Oncode Institute, Amsterdam, Netherlands., Yin J; School of Clinical Medicine, Faculty of Medicine, University of New South Wales (UNSW) Sydney, Kensington, New South Wales, Australia.; Translational Oncology Program, Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia., Dew AB; Centre for Advanced Histology & Microscopy, Peter MacCallum Cancer Centre, Parkville, Victoria, Australia., McMillan PJ; Centre for Advanced Histology & Microscopy, Peter MacCallum Cancer Centre, Parkville, Victoria, Australia.; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia.; Biological Optical Microscopy Platform, The University of Melbourne, Parkville, Victoria, Australia., Goldstein LD; School of Clinical Medicine, Faculty of Medicine, University of New South Wales (UNSW) Sydney, Kensington, New South Wales, Australia.; Data Science Platform, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia., Deveson IW; School of Clinical Medicine, Faculty of Medicine, University of New South Wales (UNSW) Sydney, Kensington, New South Wales, Australia.; Genomics and Inherited Disease Program, Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia., Croucher DR; School of Clinical Medicine, Faculty of Medicine, University of New South Wales (UNSW) Sydney, Kensington, New South Wales, Australia.; Translational Oncology Program, Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia., Samuel MS; Centre for Cancer Biology, An Alliance of SA Pathology and University of South Australia, Adelaide, South Australia, Australia.; Basil Hetzel Institute for Translational Health Research, Queen Elizabeth Hospital, Woodville South, South Australia, Australia., Sim HW; Cancer Ecosystems Program, Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia.; School of Clinical Medicine, Faculty of Medicine, University of New South Wales (UNSW) Sydney, Kensington, New South Wales, Australia.; NHMRC Clinical Trials Centre, University of Sydney, Camperdown, New South Wales, Australia.; Department of Medical Oncology, Chris O'Brien Lifehouse, Camperdown, New South Wales, Australia., Batten M; Cancer Ecosystems Program, Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia., Chantrill L; Cancer Ecosystems Program, Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia.; Department of Medical Oncology, Illawarra Shoalhaven Local Health District, Wollongong, New South Wales, Australia., Grimmond SM; Centre for Cancer Research and Department of Clinical Pathology, The University of Melbourne, Parkville, Victoria, Australia., Gill AJ; Cancer Ecosystems Program, Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia.; NSW Health Pathology, Department of Anatomical Pathology, Royal North Shore Hospital, St Leonards, New South Wales, Australia.; Sydney Medical School, University of Sydney, Camperdown, New South Wales, Australia., Samra J; Department of Surgery, Royal North Shore Hospital, St Leonards, New South Wales, Australia., Jeffry Evans TR; Cancer Research UK Beatson Institute, Glasgow, UK.; School of Cancer Sciences, Institute of Cancer Sciences, University of Glasgow, Glasgow, UK., Sasaki T; Department of Biochemistry, Faculty of Medicine, Oita University, Oita, Japan., Phan TG; School of Clinical Medicine, Faculty of Medicine, University of New South Wales (UNSW) Sydney, Kensington, New South Wales, Australia.; Precision Immunology Program, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia., Swarbrick A; Cancer Ecosystems Program, Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia.; School of Clinical Medicine, Faculty of Medicine, University of New South Wales (UNSW) Sydney, Kensington, New South Wales, Australia., Sansom OJ; Cancer Research UK Beatson Institute, Glasgow, UK.; School of Cancer Sciences, Institute of Cancer Sciences, University of Glasgow, Glasgow, UK., Morton JP; Cancer Research UK Beatson Institute, Glasgow, UK.; School of Cancer Sciences, Institute of Cancer Sciences, University of Glasgow, Glasgow, UK., Pajic M; School of Clinical Medicine, Faculty of Medicine, University of New South Wales (UNSW) Sydney, Kensington, New South Wales, Australia.; Translational Oncology Program, Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia., Parker BL; Department of Anatomy and Physiology, University of Melbourne, Parkville, Victoria, Australia., Herrmann D; Cancer Ecosystems Program, Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia.; School of Clinical Medicine, Faculty of Medicine, University of New South Wales (UNSW) Sydney, Kensington, New South Wales, Australia., Cox TR; Cancer Ecosystems Program, Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia.; School of Clinical Medicine, Faculty of Medicine, University of New South Wales (UNSW) Sydney, Kensington, New South Wales, Australia., Timpson P; Cancer Ecosystems Program, Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia.; School of Clinical Medicine, Faculty of Medicine, University of New South Wales (UNSW) Sydney, Kensington, New South Wales, Australia.
Jazyk: angličtina
Zdroj: Science advances [Sci Adv] 2024 Jul 05; Vol. 10 (27), pp. eadl1197. Date of Electronic Publication: 2024 Jul 03.
DOI: 10.1126/sciadv.adl1197
Abstrakt: Pancreatic ductal adenocarcinoma (PDAC) is characterized by increasing fibrosis, which can enhance tumor progression and spread. Here, we undertook an unbiased temporal assessment of the matrisome of the highly metastatic KPC ( Pdx1-Cre , LSL-Kras G12D/+ , LSL-Trp53 R172H/+ ) and poorly metastatic KP fl C ( Pdx1-Cre , LSL-Kras G12D/+ , Trp53 fl/+ ) genetically engineered mouse models of pancreatic cancer using mass spectrometry proteomics. Our assessment at early-, mid-, and late-stage disease reveals an increased abundance of nidogen-2 (NID2) in the KPC model compared to KP fl C, with further validation showing that NID2 is primarily expressed by cancer-associated fibroblasts (CAFs). Using biomechanical assessments, second harmonic generation imaging, and birefringence analysis, we show that NID2 reduction by CRISPR interference (CRISPRi) in CAFs reduces stiffness and matrix remodeling in three-dimensional models, leading to impaired cancer cell invasion. Intravital imaging revealed improved vascular patency in live NID2-depleted tumors, with enhanced response to gemcitabine/Abraxane. In orthotopic models, NID2 CRISPRi tumors had less liver metastasis and increased survival, highlighting NID2 as a potential PDAC cotarget.
Databáze: MEDLINE