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

Pereira, B.A.; Ritchie, S.; Chambers, C.R.; Gordon, K.A.; Magenau, A.; Murphy, K.J.; Nobis, M.; Tyma, V.M.; Liew, Y.F.; Lucas, M.C.; Naeini, M.M.; Barkauskas, D.S.; Chacon-Fajardo, D.; Howell, A.E.; Parker, A.L.; Warren, S.C.; Reed, D.A.; Lee, V.; Metcalf, X.L.; Lee, Y.K.; et al.

doi:10.1126/sciadv.adl1197

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

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2024

Authors

Pereira, B.A.

Ritchie, S.

Chambers, C.R.

Gordon, K.A.

Magenau, A.

Murphy, K.J.

Nobis, M.

Tyma, V.M.

Liew, Y.F.

Lucas, M.C.

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Journal article

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Science Advances, 2024; 10(27):eadl1197-1-eadl1197-25

Statement of Responsibility

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

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 KPfl C (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 KPfl 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.

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© 2024 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY).

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http://dx.doi.org/10.1126/sciadv.adl1197

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https://hdl.handle.net/2440/143151

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

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