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

• Published in: Science advances Vol. 10; no. 27; p. eadl1197
• Main Authors: Pereira, Brooke A, Ritchie, Shona, Chambers, Cecilia R, Gordon, Katie A, Magenau, Astrid, Murphy, Kendelle J, Nobis, Max, Tyma, Victoria M, Liew, Ying Fei, Lucas, Morghan C, Naeini, Marjan M, Barkauskas, Deborah S, Chacon-Fajardo, Diego, Howell, Anna E, Parker, Amelia L, Warren, Sean C, Reed, Daniel A, Lee, Victoria, Metcalf, Xanthe L, Lee, Young Kyung, O'Regan, Luke P, Zhu, Jessie, Trpceski, Michael, Fontaine, Angela R M, Stoehr, Janett, Rouet, Romain, Lin, Xufeng, Chitty, Jessica L, Porazinski, Sean, Wu, Sunny Z, Filipe, Elysse C, Cadell, Antonia L, Holliday, Holly, Yang, Jessica, Papanicolaou, Michael, Lyons, Ruth J, Zaratzian, Anaiis, Tayao, Michael, Da Silva, Andrew, Vennin, Claire, Yin, Julia, Dew, Alysha B, McMillan, Paul J, Goldstein, Leonard D, Deveson, Ira W, Croucher, David R, Samuel, Michael S, Sim, Hao-Wen, Batten, Marcel, Chantrill, Lorraine, Grimmond, Sean M, Gill, Anthony J, Samra, Jaswinder, Jeffry Evans, Thomas R, Sasaki, Takako, Phan, Tri G, Swarbrick, Alexander, Sansom, Owen J, Morton, Jennifer P, Pajic, Marina, Parker, Benjamin L, Herrmann, David, Cox, Thomas R, Timpson, Paul
• Format: Journal Article
• Language: English
• Published: United States American Association for the Advancement of Science 05.07.2024
• Subjects: Animals; Biomedicine and Life Sciences; Calcium-Binding Proteins - genetics; Calcium-Binding Proteins - metabolism; Cancer; Cancer-Associated Fibroblasts - metabolism; Cancer-Associated Fibroblasts - pathology; Carcinoma, Pancreatic Ductal - genetics; Carcinoma, Pancreatic Ductal - metabolism; Carcinoma, Pancreatic Ductal - pathology; Cell Adhesion Molecules; Cell Biology; Cell Line, Tumor; Deoxycytidine - analogs & derivatives; Deoxycytidine - pharmacology; Disease Models, Animal; Fibrosis; Gemcitabine; Humans; Mice; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - pathology; Proteomics - methods; SciAdv r-articles
• ISSN: 2375-2548; 2375-2548
• DOI: 10.1126/sciadv.adl1197

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 ( , , ) and poorly metastatic KP C ( , , ) 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 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.