时间解析蛋白质组学将 nidogen-2 确定为胰腺癌中调节纤维化和治疗反应的共同靶标。
Temporally resolved proteomics identifies nidogen-2 as a cotarget in pancreatic cancer that modulates fibrosis and therapy response.
发表日期：2024 Jul 05
作者：
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, , , Marina Pajic, Benjamin L Parker, David Herrmann, Thomas R Cox, Paul Timpson
来源：
CLINICAL PHARMACOLOGY & THERAPEUTICS
摘要：
胰腺导管腺癌（PDAC）的特点是纤维化增加，这会促进肿瘤的进展和扩散。在这里，我们对经过基因工程改造的高转移 KPC（Pdx1-Cre、LSL-KrasG12D/、LSL-Trp53R172H/）和低转移 KPflC（Pdx1-Cre、LSL-KrasG12D/、Trp53fl/）的基质体进行了公正的时间评估。使用质谱蛋白质组学建立胰腺癌小鼠模型。我们对早期、中期和晚期疾病的评估显示，与 KPflC 相比，KPC 模型中 nidogen-2 (NID2) 的丰度有所增加，进一步验证表明 NID2 主要由癌症相关成纤维细胞 (CAF) 表达。通过生物力学评估、二次谐波成像和双折射分析，我们发现 CAF 中 CRISPR 干扰 (CRISPRi) 减少 NID2 会降低三维模型中的刚度和基质重塑，从而导致癌细胞侵袭受损。活体成像显示 NID2 耗尽的活体肿瘤的血管通畅性得到改善，并且对吉西他滨/Abraxane 的反应增强。在原位模型中，NID2 CRISPRi 肿瘤的肝转移较少，存活率较高，这凸显了 NID2 作为潜在的 PDAC 共同靶标。
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.