%0 Journal Article
%T Temporally resolved proteomics identifies nidogen-2 as a cotarget in pancreatic cancer that modulates fibrosis and therapy response.
%A Pereira BA
%A Ritchie S
%A Chambers CR
%A Gordon KA
%A Magenau A
%A Murphy KJ
%A Nobis M
%A Tyma VM
%A Liew YF
%A Lucas MC
%A Naeini MM
%A Barkauskas DS
%A Chacon-Fajardo D
%A Howell AE
%A Parker AL
%A Warren SC
%A Reed DA
%A Lee V
%A Metcalf XL
%A Lee YK
%A O'Regan LP
%A Zhu J
%A Trpceski M
%A Fontaine ARM
%A Stoehr J
%A Rouet R
%A Lin X
%A Chitty JL
%A Porazinski S
%A Wu SZ
%A Filipe EC
%A Cadell AL
%A Holliday H
%A Yang J
%A Papanicolaou M
%A Lyons RJ
%A Zaratzian A
%A Tayao M
%A Da Silva A
%A Vennin C
%A Yin J
%A Dew AB
%A McMillan PJ
%A Goldstein LD
%A Deveson IW
%A Croucher DR
%A Samuel MS
%A Sim HW
%A Batten M
%A Chantrill L
%A Grimmond SM
%A Gill AJ
%A Samra J
%A Jeffry Evans TR
%A Sasaki T
%A Phan TG
%A Swarbrick A
%A Sansom OJ
%A Morton JP
%A  
%A  
%A Pajic M
%A Parker BL
%A Herrmann D
%A Cox TR
%A Timpson P
%J Sci Adv
%V 10
%N 27
%D 2024 Jul 5
%M 38959305
%F 14.957
%R 10.1126/sciadv.adl1197
%X 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.