Molecular Oncology, Centro Nacional de Investigaciones Oncológicas (CNIO), 28029 Madrid, Spain.
Bioinformatics Unit, Structural Biology and Biocomputing Programmes, CNIO, 28029 Madrid, Spain.
Proc Natl Acad Sci U S A. 2018 Feb 6;115(6):E1147-E1156. doi: 10.1073/pnas.1717802115. Epub 2018 Jan 19.
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, , a member of the serum amyloid A (SAA) apolipoprotein family, is a key mediator of the protumorigenic activity of PDGFRα CAFs. Whereas -competent CAFs stimulate the growth of tumor cells in an orthotopic model, -null CAFs inhibit tumor growth. Saa3 also plays a role in the cross talk between CAFs and tumor cells. Ablation of in pancreatic tumor cells makes them insensitive to the inhibitory effect of -null CAFs. As a consequence, germline ablation of 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, , the ortholog of murine Saa3, is overexpressed in human CAFs. Moreover, high levels of 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.
胰腺导管腺癌 (PDAC) 的特征是存在丰富的促结缔组织增生性基质，主要由癌相关成纤维细胞 (CAFs) 组成。人们普遍认为 CAFs 刺激肿瘤进展，并可能与耐药性和免疫抑制有关。在这里，我们比较了从基因工程小鼠 PDAC 肿瘤中分离的 PDGFRα CAFs 的转录谱与正常胰腺成纤维细胞的转录谱，以鉴定可能与其促肿瘤特性相关的基因。我们报告说，差异表达最显著的基因是血清淀粉样蛋白 A (SAA) 载脂蛋白家族的成员，是 PDGFRα CAFs 促肿瘤活性的关键介质。虽然有能力的 CAFs 刺激肿瘤细胞在原位模型中的生长，但 -null CAFs 抑制肿瘤生长。Saa3 也在 CAFs 和肿瘤细胞之间的串扰中发挥作用。在胰腺肿瘤细胞中敲除 会使它们对 -null CAFs 的抑制作用不敏感。因此，在小鼠中敲除 并不能阻止 PDAC 的发展。Saa3 在 CAFs 中的促肿瘤活性是通过 Mpp6 介导的，Mpp6 是外周膜相关鸟苷酸激酶 (MAGUK) 棕榈酰化膜蛋白亚家族的成员。最后，我们询问这些观察结果是否可以转化为人类情况。事实上，鼠 Saa3 的同源物 在人 CAFs 中过表达。此外，基质成分中 的高表达水平与较差的生存相关。这些发现支持这样一种概念，即选择性抑制 CAFs 中的 SAA1 可能为 PDAC 患者提供潜在的治疗益处。
