Saa3 is a key mediator of the protumorigenic properties of cancer-associated fibroblasts in pancreatic tumors
Author
Djurec, Magdolna; Graña, Osvaldo; Lee, Albert; Troulé, Kevin; Espinet, Elisa; Cabras, Lavinia; Navas, Carolina; Blasco, María Teresa; Martín-Díaz, Laura; Burdiel, Miranda; Li, Jing; Liu, Zhaoqi; Vallespinós, Mireia; Sanchez-Bueno, Francisco; Sprick, Martin R.; Trumpp, Andreas; Sainz, Bruno; Al-Shahrour, Fátima; Rabadan, Raul; Guerra, Carmen; Barbacid, MarianoEntity
UAM. Departamento de BioquímicaPublisher
The National Academies of Sciences, Engineering, and MedicineDate
2018-02-06Citation
10.1073/pnas.1717802115
Proceedings of the National Academy of Sciences of the United States of America 115.6 (2018): E1147-E1156.
ISSN
0027-8424 (print); 1091-6490 (online)DOI
10.1073/pnas.1717802115Funded by
This work was supported by European Research Council Grants ERC-AG/250297-RAS AHEAD and ERC-AG/695566-THERACAN, Spanish Ministry of Economy and Competitiveness Grant SAF2014-59864-R, and Asociación Española contra el Cáncer Grant GC16173694BARB (to M. Barbacid). M.D. was supported by a fellowship from La Caixa International Fellowship Program. M. Barbacid is the recipient of an Endowed Chair from the AXA Research FundProject
info:eu-repo/grantAgreement/EC/FP7/250297; info:eu-repo/grantAgreement/EC/H2020/695566/EU//THERACAN; Gobierno de España. SAF2014-59864-REditor's Version
https://doi.org/10.1073/pnas.1717802115Subjects
CAFs; Mouse models; PDAC; Saa3; Stroma; MedicinaRights
© 2018 PNASEsta obra está bajo una licencia de Creative Commons Reconocimiento-NoComercial-SinObraDerivada 4.0 Internacional.
Abstract
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.
Files in this item
Google Scholar:Djurec, Magdolna
-
Graña, Osvaldo
-
Lee, Albert
-
Troulé, Kevin
-
Espinet, Elisa
-
Cabras, Lavinia
-
Navas, Carolina
-
Blasco, María Teresa
-
Martín-Díaz, Laura
-
Burdiel, Miranda
-
Li, Jing
-
Liu, Zhaoqi
-
Vallespinós, Mireia
-
Sanchez-Bueno, Francisco
-
Sprick, Martin R.
-
Trumpp, Andreas
-
Sainz, Bruno
-
Al-Shahrour, Fátima
-
Rabadan, Raul
-
Guerra, Carmen
-
Barbacid, Mariano
This item appears in the following Collection(s)
Related items
Showing items related by title, author, creator and subject.
-
Exploiting oxidative phosphorylation to promote the stem and immunoevasive properties of pancreatic cancer stem cells
Valle, Sandra; Alcalá, Sonia; Martin-Hijano, Laura; Cabezas-Sáinz, Pablo; Navarro, Diego; Muñoz, Edurne Ramos; Yuste, Lourdes; Tiwary, Kanishka; Walter, Karolin; Ruiz-Cañas, Laura; Alonso-Nocelo, Marta; Rubiolo, Juan A.; González-Arnay, Emilio; Heeschen, Christopher; Garcia-Bermejo, Laura; Hermann, Patrick C.; Sánchez, Laura; Sancho, Patricia; Fernández-Moreno, Miguel Ángel; Sainz, Bruno
2020-10-16 -
Cancer-associated fibroblast and M2 macrophage markers together predict outcome in colorectal cancer patients
Herrera, Mercedes A.; Herrera, Alberto F.; Domínguez Muñoz, Gemma; Silva, Javier M.; García, Vanesa Quiroga; García, José Miguel Jurado; Gómez, Irene; Soldevilla, Beatriz; Muñoz, Concepción Morales; Provencio Pulla, Mariano; Campos-Martín, Yolanda; Garcia de Herreros, Antonio; Casal, Ignacio; Bonilla, Félix; Peña, Cristina
2013-04-01