2026-06-14T03:46:24Zhttps://repisalud.isciii.es/rest/oai/request

oai:repisalud.isciii.es:20.500.12105/83052024-11-29T13:56:07Zcom_20.500.12105_2173com_20.500.12105_2051col_20.500.12105_19597

00925njm 22002777a 4500 dc Djurec, Magdolna author Graña Castro, Osvaldo author Lee, Albert author Troulé, Kevin author Espinet, Elisa author Cabras, Lavinia author Navas, Carolina author Blasco, María Teresa author Martín-Díaz, Laura author Burdiel, Miranda author Li, Jing author Liu, Zhaoqi author Vallespinós, Mireia author Sanchez-Bueno, Francisco author Sprick, Martin R author Trumpp, Andreas author Sainz, Bruno author Al-Shahrour, Fatima author Rabadan, Raul author Guerra, Carmen author Barbacid, Mariano author 2018-02-06 Pancreatic ductal adenocarcinoma (PDAC) is characterized by the presence of abundant desmoplastic stroma primarily composed of cancer-associated fibroblasts (CAFs). It is generally accepted that CAFs stimulate tumor progression and might be implicated in drug resistance and immunosuppression. Here, we have compared the transcriptional profile of PDGFRα+ CAFs isolated from genetically engineered mouse PDAC tumors with that of normal pancreatic fibroblasts to identify genes potentially implicated in their protumorigenic properties. We report that the most differentially expressed gene, Saa3, a member of the serum amyloid A (SAA) apolipoprotein family, is a key mediator of the protumorigenic activity of PDGFRα+ CAFs. Whereas Saa3-competent CAFs stimulate the growth of tumor cells in an orthotopic model, Saa3-null CAFs inhibit tumor growth. Saa3 also plays a role in the cross talk between CAFs and tumor cells. Ablation of Saa3 in pancreatic tumor cells makes them insensitive to the inhibitory effect of Saa3-null CAFs. As a consequence, germline ablation of Saa3 does not prevent PDAC development in mice. The protumorigenic activity of Saa3 in CAFs is mediated by Mpp6, a member of the palmitoylated membrane protein subfamily of the peripheral membrane-associated guanylate kinases (MAGUK). Finally, we interrogated whether these observations could be translated to a human scenario. Indeed, SAA1, the ortholog of murine Saa3, is overexpressed in human CAFs. Moreover, high levels of SAA1 in the stromal component correlate with worse survival. These findings support the concept that selective inhibition of SAA1 in CAFs may provide potential therapeutic benefit to PDAC patients. Proc Natl Acad Sci U S A. 2018 ;115(6):E1147-E1156. 10.1073/pnas.1717802115 1091-6490 0027-8424 Proceedings of the National Academy of Sciences of the United States of America 29351990 http://hdl.handle.net/20.500.12105/8305 CAFs PDAC Saa3 mouse models stroma Saa3 is a key mediator of the protumorigenic properties of cancer-associated fibroblasts in pancreatic tumors