Temporally resolved proteomics identifies nidogen-2 as a cotarget in pancreatic cancer that modulates fibrosis and therapy response.
Brooke A PereiraShona RitchieCecilia R ChambersKatie A GordonAstrid MagenauKendelle J MurphyMax NobisVictoria M TymaYing Fei LiewMorghan C LucasMarjan Mojtabavi NaeiniDeborah S BarkauskasDiego Chacon-FajardoAnna E HowellAmelia L ParkerSean C WarrenDaniel A ReedVictoria LeeXanthe L MetcalfYoung-Kyung LeeLuke P O'ReganJessie ZhuMichael TrpceskiAngela R M KurzJanett StoehrRomain RouetXufeng LinJessica L ChittySean PorazinskiSunny Z WuElysse C FilipeAntonia L CadellHolly HollidayJessica YangMichael PapanicolaouRuth J LyonsAnaiis ZaratzianMichael TayaoAndrew Da SilvaClaire VenninJulia X YinAlysha B DewPaul J McMillanLeonard D GoldsteinIra W DevesonDavid R CroucherMichael Susithiran SamuelHao-Wen SimMarcel BattenLorraine A ChantrillSean M GrimmondAnthony J GillJaswinder SamraThomas R Jeffry EvansTakako SasakiTri Giang PhanAlexander SwarbrickOwen James SansomJennifer P Mortonnull nullnull nullMarina PajicBenjamin L ParkerDavid HerrmannThomas R CoxPaul TimpsonPublished in: Science advances (2024)
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.
Keyphrases
- mass spectrometry
- high resolution
- squamous cell carcinoma
- genome wide
- small cell lung cancer
- klebsiella pneumoniae
- liquid chromatography
- mouse model
- poor prognosis
- crispr cas
- papillary thyroid
- single cell
- capillary electrophoresis
- gas chromatography
- wild type
- genome editing
- label free
- risk assessment
- fluorescence imaging
- mesenchymal stem cells
- locally advanced
- human health
- multidrug resistant
- extracellular matrix
- smoking cessation
- wastewater treatment