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

Pereira, BA; Ritchie, S; Chambers, CR; Gordon, KA; Magenau, A; Murphy, KJ; Nobis, M; Tyma, VM; Liew, YF; Lucas, MC; Naeini, MM; Barkauskas, DS; Chacon-Fajardo, D; Howell, AE; Parker, AL; Warren, SC; Reed, DA; Lee, V; Metcalf, XL; Lee, YK; O&#39;Regan, LP; Zhu, J; Trpceski, M; Fontaine, ARM; Stoehr, J; Rouet, R; Lin, X; Chitty, JL; Porazinski, S; Wu, SZ; Filipe, EC; Cadell, AL; Holliday, H; Yang, J; Papanicolaou, M; Lyons, RJ; Zaratzian, A; Tayao, M; Da Silva, A; Vennin, C; Yin, J; Dew, AB; McMillan, PJ; Goldstein, LD; Deveson, IW; Croucher, DR; Samuel, MS; Sim, HW; Batten, M; Chantrill, L; Grimmond, SM; Gill, AJ; Samra, J; Jeffry Evans, TR; Sasaki, T; Phan, TG; Swarbrick, A; Sansom, OJ; Morton, JP; Australian Pancreatic Cancer Matrix Atlas; Australian Pancreatic Cancer Genome Initiative; Pajic, M; Parker, BL; Herrmann, D; Cox, TR; Timpson, P

Author(s): Pereira, BA; Ritchie, S; Chambers, CR; Gordon, KA; Magenau, A; Murphy, KJ; Nobis, M; Tyma, VM; Liew, YF; Lucas, MC; Naeini, MM; Barkauskas, DS; Chacon-Fajardo, D; Howell, AE; Parker, AL; Warren, SC; Reed, DA; Lee, V; Metcalf, XL; Lee, YK; O'Regan, LP; Zhu, J; Trpceski, M; Fontaine, ARM; Stoehr, J; Rouet, R; Lin, X; Chitty, JL; Porazinski, S; Wu, SZ; Filipe, EC; Cadell, AL; Holliday, H; Yang, J; Papanicolaou, M; Lyons, RJ; Zaratzian, A; Tayao, M; Da Silva, A; Vennin, C; Yin, J; Dew, AB; McMillan, PJ; Goldstein, LD; Deveson, IW; Croucher, DR; Samuel, MS; Sim, HW; Batten, M; Chantrill, L; Grimmond, SM; Gill, AJ; Samra, J; Jeffry Evans, TR; Sasaki, T; Phan, TG; Swarbrick, A; Sansom, OJ; Morton, JP; Australian Pancreatic Cancer Matrix Atlas; Australian Pancreatic Cancer Genome Initiative; Pajic, M; Parker, BL; Herrmann, D; Cox, TR; Timpson, P;
Details: Publication Year 2024-07-05,Volume 10,Issue #27,Page eadl1197
Journal Title: Science Advances
Publication Type: Research article
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
Keywords: Animals; *Pancreatic Neoplasms/metabolism/pathology/genetics; *Proteomics/methods; Mice; *Fibrosis; Humans; *Carcinoma, Pancreatic Ductal/metabolism/pathology/genetics; Cancer-Associated Fibroblasts/metabolism/pathology; Disease Models, Animal; Cell Line, Tumor; Calcium-Binding Proteins/metabolism/genetics; Gemcitabine; Deoxycytidine/analogs & derivatives/pharmacology; Cell Adhesion Molecules
Department(s): Laboratory Research
Publisher's Version: https://doi.org/10.1126/sciadv.adl1197
Open Access at Publisher's Site: https://doi.org/10.1126/sciadv.adl1197
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2024-08-27 04:40:35

Last Modified: 2024-08-27 04:48:12