Temporally resolved proteomics identifies nidogen-2 as a cotarget in pancreatic cancer that modulates fibrosis and therapy response-Reference-Cited by-同舟云学术

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

Published:2024-07-05 Issue:27 Volume:10 Page:
ISSN:2375-2548
Container-title:Science Advances
language:en
Short-container-title:Sci. Adv.

Author:

Pereira Brooke A.¹²^ORCID,Ritchie Shona¹²^ORCID,Chambers Cecilia R.¹²^ORCID,Gordon Katie A.¹²,Magenau Astrid¹²,Murphy Kendelle J.¹²^ORCID,Nobis Max¹²³^ORCID,Tyma Victoria M.¹^ORCID,Liew Ying Fei¹,Lucas Morghan C.¹²⁴⁵^ORCID,Naeini Marjan M.²⁶^ORCID,Barkauskas Deborah S.¹⁷^ORCID,Chacon-Fajardo Diego²⁸^ORCID,Howell Anna E.¹^ORCID,Parker Amelia L.¹²,Warren Sean C.¹²^ORCID,Reed Daniel A.¹²^ORCID,Lee Victoria¹^ORCID,Metcalf Xanthe L.¹^ORCID,Lee Young Kyung¹^ORCID,O’Regan Luke P.¹^ORCID,Zhu Jessie¹²,Trpceski Michael¹²^ORCID,Fontaine Angela R. M.¹²⁷^ORCID,Stoehr Janett¹^ORCID,Rouet Romain²⁹,Lin Xufeng¹⁰^ORCID,Chitty Jessica L.¹²^ORCID,Porazinski Sean²⁸,Wu Sunny Z.¹²¹¹^ORCID,Filipe Elysse C.¹²,Cadell Antonia L.²⁸^ORCID,Holliday Holly¹²¹²^ORCID,Yang Jessica¹²^ORCID,Papanicolaou Michael¹²^ORCID,Lyons Ruth J.¹,Zaratzian Anaiis¹³,Tayao Michael¹³^ORCID,Da Silva Andrew¹³,Vennin Claire¹²¹⁴¹⁵^ORCID,Yin Julia²⁸^ORCID,Dew Alysha B.¹⁶,McMillan Paul J.¹⁶¹⁷¹⁸^ORCID,Goldstein Leonard D.²¹⁰^ORCID,Deveson Ira W.²⁶^ORCID,Croucher David R.²⁸^ORCID,Samuel Michael S.¹⁹²⁰^ORCID,Sim Hao-Wen¹²²¹²²^ORCID,Batten Marcel¹^ORCID,Chantrill Lorraine¹²³^ORCID,Grimmond Sean M.²⁴^ORCID,Gill Anthony J.¹²⁵²⁶^ORCID,Samra Jaswinder²⁷,Jeffry Evans Thomas R.²⁸²⁹^ORCID,Sasaki Takako³⁰^ORCID,Phan Tri G.²³¹^ORCID,Swarbrick Alexander¹²,Sansom Owen J.²⁸²⁹^ORCID,Morton Jennifer P.²⁸²⁹^ORCID,Pajic Marina²⁸^ORCID,Parker Benjamin L.³²^ORCID,Herrmann David¹²^ORCID,Cox Thomas R.¹²^ORCID,Timpson Paul¹²^ORCID, ,

Affiliation:

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.

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-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.

Publisher

American Association for the Advancement of Science (AAAS)

Link

https://www.science.org/doi/pdf/10.1126/sciadv.adl1197

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