Pereira, Brooke A. and Ritchie, Shona and Chambers, Cecilia R. and Gordon, Katie A. and Magenau, Astrid and Murphy, Kendelle J. and Nobis, Max and Tyma, Victoria M. and Liew, Ying Fei and Lucas, Morghan C. and Naeini, Marjan M. and Barkauskas, Deborah S. and Chacon-Fajardo, Diego and Howell, Anna E. and Parker, Amelia L. and Warren, Sean C. and Reed, Daniel A. and Lee, Victoria and Metcalf, Xanthe L. and Lee, Young Kyung and O'Regan, Luke P. and Zhu, Jessie and Trpceski, Michael and Fontaine, Angela R.M. and Stoehr, Janett and Rouet, Romain and Lin, Xufeng and Chitty, Jessica L. and Porazinski, Sean and Wu, Sunny Z. and Filipe, Elysse C. and Cadell, Antonia L. and Holliday, Holly and Yang, Jessica and Papanicolaou, Michael and Lyons, Ruth J. and Zaratzian, Anaiis and Tayao, Michael and Da Silva, Andrew and Vennin, Claire and Yin, Julia and Dew, Alysha B. and McMillan, Paul J. and Goldstein, Leonard D. and Deveson, Ira W. and Croucher, David R. and Samuel, Michael S. and Sim, Hao-Wen and Batten, Marcel and Chantrill, Lorraine and Grimmond, Sean M. and Gill, Anthony J. and Samra, Jaswinder and Evans, Thomas R. Jeffry and Sasaki, Takako and Phan, Tri G. and Swarbrick, Alexander and Sansom, Owen J. and Morton, Jennifer P. and Australian Pancreatic Cancer Matrix Atlas (APMA) and Australian Pancreatic Cancer Genome Initiative (APGI) and Pajic, Marina and Parker, Benjamin L. and Herrmann, David and Cox, Thomas R. and Timpson, Paul (2024) Temporally resolved proteomics identifies nidogen-2 as a cotarget in pancreatic cancer that modulates fibrosis and therapy response. Science Advances, 10 (27): eadl1197. ISSN 2375-2548

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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.

Information
Title Temporally resolved proteomics identifies nidogen-2 as a cotarget in pancreatic cancer that modulates fibrosis and therapy response
Creators Pereira, Brooke A. and Ritchie, Shona and Chambers, Cecilia R. and Gordon, Katie A. and Magenau, Astrid and Murphy, Kendelle J. and Nobis, Max and Tyma, Victoria M. and Liew, Ying Fei and Lucas, Morghan C. and Naeini, Marjan M. and Barkauskas, Deborah S. and Chacon-Fajardo, Diego and Howell, Anna E. and Parker, Amelia L. and Warren, Sean C. and Reed, Daniel A. and Lee, Victoria and Metcalf, Xanthe L. and Lee, Young Kyung and O'Regan, Luke P. and Zhu, Jessie and Trpceski, Michael and Fontaine, Angela R.M. and Stoehr, Janett and Rouet, Romain and Lin, Xufeng and Chitty, Jessica L. and Porazinski, Sean and Wu, Sunny Z. and Filipe, Elysse C. and Cadell, Antonia L. and Holliday, Holly and Yang, Jessica and Papanicolaou, Michael and Lyons, Ruth J. and Zaratzian, Anaiis and Tayao, Michael and Da Silva, Andrew and Vennin, Claire and Yin, Julia and Dew, Alysha B. and McMillan, Paul J. and Goldstein, Leonard D. and Deveson, Ira W. and Croucher, David R. and Samuel, Michael S. and Sim, Hao-Wen and Batten, Marcel and Chantrill, Lorraine and Grimmond, Sean M. and Gill, Anthony J. and Samra, Jaswinder and Evans, Thomas R. Jeffry and Sasaki, Takako and Phan, Tri G. and Swarbrick, Alexander and Sansom, Owen J. and Morton, Jennifer P. and Australian Pancreatic Cancer Matrix Atlas (APMA) and Australian Pancreatic Cancer Genome Initiative (APGI) and Pajic, Marina and Parker, Benjamin L. and Herrmann, David and Cox, Thomas R. and Timpson, Paul
Identification Number 10.1126/sciadv.adl1197
Date 3 July 2024
Divisions College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Publisher American Association for the Advancement of Science
Additional Information This study was supported by the National Health and Medical Research Council (NHMRC; 1136974, 1158590, 1160022, 1162556, 1188208, 2000937, 2003310, 2010330, 2012837, 2013881, 2016930, 2018440, 2019139, and 2019843), Cancer Council (RG 23-11, RG 19-09, RG 21-12, and RG 23-07), Cancer Institute NSW (CINSW; ECF012, ECF011, ECF1309, ECF1384, CDF1173, CDF1167, and TPG2100). Cancer Australia (2021412), Tour de Cure (RSP-509-FY2023), St. Vincent’s Clinic Foundation, UNSW SPHERE, Perpetual (IPAP2022-0736), Sydney Catalyst, an Australian Cancer Research Foundation (ACRF) infrastructure grant (INCITe Centre), and Suttons family and Len Ainsworth foundation philanthropy. This work was made possible by Pankind grants (formally known as Avner Australian Pancreatic Cancer Foundation; R3-PT accelerator, PT.GIMR.16 accelerator, R4-DH, and SP.GIMR.18 accelerator). P.T. was supported by a National Health and Medical Research Council (NHMRC) Fellowship (1136974 and 2016930) and a Len Ainsworth Fellowship. T.R.C. was supported by the NHMRC Career Development Fellowship (1158590). A.S. (2018440) and M.Paj. (1162556) were supported by a NHMRC Investigator Fellowships. M.Paj. was supported by a Snow Medical Fellowship (SF2020-79). D.R.C. was supported by a National Breast Cancer Foundation (NBCF) Fellowship (IIRS-20-032). B.A.P. (ECF1309), K.J.M. (ECF1384), D.H. (ECF011), and M.N. (ECF012) were supported by a CINSW Early Career Research Fellowship. S.P. (CDF1173) and A.L.P. (CDF1167) were supported by a CINSW Mid Career Research Fellowship. A.R.M.F. and D.S.B. were supported by ACRF/CINSW Imaging Fellowships. R.R. was supported by an ARC DECRA Fellowship (DE190100985). M.S.S. was supported by an Australian Breast Cancer Research Fellowship from The Hospital Research Foundation. S.R. was supported by a UNSW International PhD scholarship. K.A.G. was supported by a Tour de Cure PhD Scholarship. C.R.C. and D.A.R. were supported by a Baxter Family Postgraduate scholarship. J.Z. was supported by a UNSW SPHERE Cancer CAG PhD scholarship. M.T. was supported by a White Walker PhD scholarship. A.L.C. was supported by a Pancare Phil Sly Research Scholarship.
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