2024-03-29T13:09:22Zhttp://repisalud.isciii.es/oai/requestoai:repisalud.isciii.es:20.500.12105/83052023-08-31T06:50:28Zcom_20.500.12105_2174com_20.500.12105_2051com_20.500.12105_2173col_20.500.12105_2175
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.
0027-8424
http://hdl.handle.net/20.500.12105/8305
29351990
10.1073/pnas.1717802115
1091-6490
Proceedings of the National Academy of Sciences of the United States of America
CAFs
PDAC
Saa3
mouse models
stroma
Saa3 is a key mediator of the protumorigenic properties of cancer-associated fibroblasts in pancreatic tumors