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

  • Sci Adv. 2024 Jul 5;10(27):eadl1197. doi: 10.1126/sciadv.adl1197.
Brooke A Pereira  1  2 ,  Shona Ritchie  1  2 ,  Cecilia R Chambers  1  2 ,  Katie A Gordon  1  2 ,  Astrid Magenau  1  2 ,  Kendelle J Murphy  1  2 ,  Max Nobis  1  2  3 ,  Victoria M Tyma  1 ,  Ying Fei Liew  1 ,  Morghan C Lucas  1  2  4  5 ,  Marjan M Naeini  2  6 ,  Deborah S Barkauskas  1  7 ,  Diego Chacon-Fajardo  2  8 ,  Anna E Howell  1 ,  Amelia L Parker  1  2 ,  Sean C Warren  1  2 ,  Daniel A Reed  1  2 ,  Victoria Lee  1 ,  Xanthe L Metcalf  1 ,  Young Kyung Lee  1 ,  Luke P O'Regan  1 ,  Jessie Zhu  1  2 ,  Michael Trpceski  1  2 ,  Angela R M Fontaine  1  2  7 ,  Janett Stoehr  1 ,  Romain Rouet  2  9 ,  Xufeng Lin  10 ,  Jessica L Chitty  1  2 ,  Sean Porazinski  2  8 ,  Sunny Z Wu  1  2  11 ,  Elysse C Filipe  1  2 ,  Antonia L Cadell  2  8 ,  Holly Holliday  1  2  12 ,  Jessica Yang  1  2 ,  Michael Papanicolaou  1  2 ,  Ruth J Lyons  1 ,  Anaiis Zaratzian  13 ,  Michael Tayao  13 ,  Andrew Da Silva  13 ,  Claire Vennin  1  2  14  15 ,  Julia Yin  2  8 ,  Alysha B Dew  16 ,  Paul J McMillan  16  17  18 ,  Leonard D Goldstein  2  10 ,  Ira W Deveson  2  6 ,  David R Croucher  2  8 ,  Michael S Samuel  19  20 ,  Hao-Wen Sim  1  2  21  22 ,  Marcel Batten  1 ,  Lorraine Chantrill  1  23 ,  Sean M Grimmond  24 ,  Anthony J Gill  1  25  26 ,  Jaswinder Samra  27 ,  Thomas R Jeffry Evans  28  29 ,  Takako Sasaki  30 ,  Tri G Phan  2  31 ,  Alexander Swarbrick  1  2 ,  Owen J Sansom  28  29 ,  Jennifer P Morton  28  29 ,  Australian Pancreatic Cancer Matrix Atlas (APMA) ,  Australian Pancreatic Cancer Genome Initiative (APGI) ,  Marina Pajic  2  8 ,  Benjamin L Parker  32 ,  David Herrmann  1  2 ,  Thomas R Cox  1  2 ,  Paul Timpson  1  2
Affiliations
  • 1. Cancer Ecosystems Program, Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia.
  • 2. School of Clinical Medicine, Faculty of Medicine, University of New South Wales (UNSW) Sydney, Kensington, New South Wales, Australia.
  • 3. Intravital Imaging Expertise Center, VIB Center for Cancer Biology, VIB, Leuven, Belgium.
  • 4. Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology, Barcelona, Spain.
  • 5. Universitat Pompeu Fabra (UPF), Barcelona, Spain.
  • 6. Genomics and Inherited Disease Program, Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia.
  • 7. ACRF INCITe Intravital Imaging Centre, Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia.
  • 8. Translational Oncology Program, Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia.
  • 9. Immune Biotherapies Program, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.
  • 10. Data Science Platform, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.
  • 11. Genentech Inc., South San Francisco, CA, USA.
  • 12. Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney, Kensington, New South Wales, Australia.
  • 13. Histopathology Platform, Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia.
  • 14. Division of Molecular Pathology, Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, Netherlands.
  • 15. Oncode Institute, Amsterdam, Netherlands.
  • 16. Centre for Advanced Histology & Microscopy, Peter MacCallum Cancer Centre, Parkville, Victoria, Australia.
  • 17. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia.
  • 18. Biological Optical Microscopy Platform, The University of Melbourne, Parkville, Victoria, Australia.
  • 19. Centre for Cancer Biology, An Alliance of SA Pathology and University of South Australia, Adelaide, South Australia, Australia.
  • 20. Basil Hetzel Institute for Translational Health Research, Queen Elizabeth Hospital, Woodville South, South Australia, Australia.
  • 21. NHMRC Clinical Trials Centre, University of Sydney, Camperdown, New South Wales, Australia.
  • 22. Department of Medical Oncology, Chris O'Brien Lifehouse, Camperdown, New South Wales, Australia.
  • 23. Department of Medical Oncology, Illawarra Shoalhaven Local Health District, Wollongong, New South Wales, Australia.
  • 24. Centre for Cancer Research and Department of Clinical Pathology, The University of Melbourne, Parkville, Victoria, Australia.
  • 25. NSW Health Pathology, Department of Anatomical Pathology, Royal North Shore Hospital, St Leonards, New South Wales, Australia.
  • 26. Sydney Medical School, University of Sydney, Camperdown, New South Wales, Australia.
  • 27. Department of Surgery, Royal North Shore Hospital, St Leonards, New South Wales, Australia.
  • 28. Cancer Research UK Beatson Institute, Glasgow, UK.
  • 29. School of Cancer Sciences, Institute of Cancer Sciences, University of Glasgow, Glasgow, UK.
  • 30. Department of Biochemistry, Faculty of Medicine, Oita University, Oita, Japan.
  • 31. Precision Immunology Program, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.
  • 32. Department of Anatomy and Physiology, University of Melbourne, Parkville, Victoria, Australia.
PMID: 38959305 DOI: 10.1126/sciadv.adl1197
Abstract

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-KrasG12D/+, LSL-Trp53R172H/+) and poorly metastatic KPflC (Pdx1-Cre, LSL-KrasG12D/+, Trp53fl/+) 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 KPflC, 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.

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