ACSL3-PAI-1 signaling axis mediates tumor-stroma cross-talk promoting pancreatic cancer progression.
ACSL3-PAI-1 signaling axis mediates tumor-stroma cross-talk promoting pancreatic cancer progression.
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DOI：
10.1126/sciadv.abb9200
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发表时间：
2020-10
期刊：
影响因子：
13.6
通讯作者：
Konstantinidou G
中科院分区：
文献类型：
--
作者：
Rossi Sebastiano M;Pozzato C;Saliakoura M;Yang Z;Peng RW;Galiè M;Oberson K;Simon HU;Karamitopoulou E;Konstantinidou G
派-1的药理学抑制强烈增强针对PDAC的化学和免疫应答。胰腺导管腺癌（PDAC）的特征是显著的纤维化和低免疫原性，这些特征与治疗耐药性和不良临床结局有关。因此，了解PDAC如何调节促结缔组织增生和免疫基质成分具有重要的临床意义。我们发现酰基辅酶A合成酶长链3（ACSL 3）在PDAC中上调，并与纤维化增加相关。我们的体内结果表明，Acsl 3敲除阻碍PDAC进展，显著减少肿瘤纤维化和肿瘤浸润免疫抑制细胞，并增加细胞毒性T细胞浸润。这种作用至少部分是由于肿瘤细胞的纤溶酶原激活物抑制剂-1（派-1）分泌减少。因此，派-1在PDAC中的表达与纤维化和免疫抑制的标志物正相关，并预测较差的患者存活率。我们发现派-1的药理学抑制强烈增强了对PDAC的化疗和免疫应答，增加了小鼠的存活率。因此，我们的结果揭示了ACSL 3-派-1信号传导是PDAC进展的必要条件，具有可药用属性。
Pharmacological inhibition of PAI-1 strongly enhances chemo- and immunotherapeutic response against PDAC. Pancreatic ductal adenocarcinoma (PDAC) is characterized by marked fibrosis and low immunogenicity, features that are linked to treatment resistance and poor clinical outcomes. Therefore, understanding how PDAC regulates the desmoplastic and immune stromal components is of great clinical importance. We found that acyl-CoA synthetase long-chain 3 (ACSL3) is up-regulated in PDAC and correlates with increased fibrosis. Our in vivo results show that Acsl3 knockout hinders PDAC progression, markedly reduces tumor fibrosis and tumor-infiltrating immunosuppressive cells, and increases cytotoxic T cell infiltration. This effect is, at least in part, due to decreased plasminogen activator inhibitor–1 (PAI-1) secretion from tumor cells. Accordingly, PAI-1 expression in PDAC positively correlates with markers of fibrosis and immunosuppression and predicts poor patient survival. We found that PAI-1 pharmacological inhibition strongly enhances chemo- and immunotherapeutic response against PDAC, increasing survival of mice. Thus, our results unveil ACSL3–PAI-1 signaling as a requirement for PDAC progression with druggable attributes.
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影响因子：
28.2
作者：
Incio J;Liu H;Suboj P;Chin SM;Chen IX;Pinter M;Ng MR;Nia HT;Grahovac J;Kao S;Babykutty S;Huang Y;Jung K;Rahbari NN;Han X;Chauhan VP;Martin JD;Kahn J;Huang P;Desphande V;Michaelson J;Michelakos TP;Ferrone CR;Soares R;Boucher Y;Fukumura D;Jain RK
通讯作者：
Jain RK
影响因子：
5.6
作者：
Ghosh, Asish K.;Vaughan, Douglas E.
通讯作者：
Vaughan, Douglas E.
影响因子：
5.7
作者：
Fang H;Jin J;Huang D;Yang F;Guan X
通讯作者：
Guan X
影响因子：
64.8
作者：
JONSSON, J;CARLSSON, L;EDLUND, H
通讯作者：
EDLUND, H
影响因子：
5.7
作者：
Flevaris, Panagiotis;Vaughan, Douglas
通讯作者：
Vaughan, Douglas