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Proc Natl Acad Sci U S A. 2018 Feb 6;115(6):E1147-E1156. doi: 10.1073/pnas.1717802115. Epub 2018 Jan 19.

Saa3 is a key mediator of the protumorigenic properties of cancer-associated fibroblasts in pancreatic tumors.

Author information

1
Molecular Oncology, Centro Nacional de Investigaciones Oncológicas (CNIO), 28029 Madrid, Spain.
2
Bioinformatics Unit, Structural Biology and Biocomputing Programmes, CNIO, 28029 Madrid, Spain.
3
Department of Systems Biology, Columbia University Medical Center, New York, NY 10032.
4
Divison of Stem Cells and Cancer, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
5
Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM), 69120 Heidelberg, Germany.
6
Department of Biochemistry, School of Medicine, Autonomous University of Madrid, 28018 Madrid, Spain.
7
Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), 28034 Madrid, Spain.
8
Department of Surgery, Clinical University Hospital Virgen Arrixaca, Murcian Institute of Biomedical Investigation (IMIB), 30120 Murcia, Spain.
9
Molecular Oncology, Centro Nacional de Investigaciones Oncológicas (CNIO), 28029 Madrid, Spain; mcguerra@cnio.es mbarbacid@cnio.es.

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.

KEYWORDS:

CAFs; PDAC; Saa3; mouse models; stroma

PMID:
29351990
PMCID:
PMC5819438
DOI:
10.1073/pnas.1717802115
[Indexed for MEDLINE]
Free PMC Article

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