EMT alterations in the solute carrier landscape uncover SLC22A10/A15 imposed vulnerabilities in pancreatic cancer.
EMT alterations in the solute carrier landscape uncover SLC22A10/A15 imposed vulnerabilities in pancreatic cancer.
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DOI：
10.1016/j.isci.2022.104193
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发表时间：
2022-05-20
期刊：
影响因子：
5.8
通讯作者：
Govindarajan, Rajgopal
中科院分区：
文献类型：
--
作者：
Nayak, Debasis;Weadick, Brenna;Persaud, Avinash K.;Raj, Radhika;Shakya, Reena;Li, Junan;Campbell, Moray J.;Govindarajan, Rajgopal
膜结合溶质载体（SLC）在肿瘤转分化过程中的参与尚不清楚。在这里，我们检查了胰腺癌细胞上皮间质转化 (EMT) 期间 SLC 景观的变化。我们发现，来自有机阴离子/阳离子转运蛋白家族的两种 SLC，SLC22A10 和 SLC22A15，通过干扰素 (IFN) α 和 γ 信号激活受体酪氨酸激酶样孤儿受体 1 (ROR1) 表达，有利于 EMT。此外，SLC22A10和SLC22A15允许肿瘤细胞积累谷胱甘肽，通过IFNα/γ-ROR1轴支持EMT。此外，泛SLC22A抑制剂lesinurad可减少EMT诱导的转移和吉西他滨化疗耐药性，从而延长胰腺癌小鼠模型的生存期，从而确定人类PDAC的新弱点。综合转运组分析确定 PDAC EMT 期间的关键 SLC 改变 SLC22A10 和 SLC22A15 触发 IFN 信号传导，促进 PDAC 侵袭性 SLC22A10 和 SLC22A15 促进谷胱甘肽积累，促进 IFN 信号传导 Lesinurad 阻止了 PDAC 小鼠模型中 SLC22A10/15 的不利影响免疫学；癌症
The involvement of membrane-bound solute carriers (SLCs) in neoplastic transdifferentiation processes is poorly defined. Here, we examined changes in the SLC landscape during epithelial-mesenchymal transition (EMT) of pancreatic cancer cells. We show that two SLCs from the organic anion/cation transporter family, SLC22A10 and SLC22A15, favor EMT via interferon (IFN) α and γ signaling activation of receptor tyrosine kinase-like orphan receptor 1 (ROR1) expression. In addition, SLC22A10 and SLC22A15 allow tumor cell accumulation of glutathione to support EMT via the IFNα/γ-ROR1 axis. Moreover, a pan-SLC22A inhibitor lesinurad reduces EMT-induced metastasis and gemcitabine chemoresistance to prolong survival in mouse models of pancreatic cancer, thus identifying new vulnerabilities for human PDAC. Comprehensive transportome analysis identifies key SLC alterations during PDAC EMT SLC22A10 and SLC22A15 trigger IFN signaling to promote PDAC aggressiveness SLC22A10 and SLC22A15 facilitate glutathione accumulation to promote IFN signaling Lesinurad impeded the SLC22A10/15 adverse effects in PDAC mouse models Biological sciences; Immunology; Cancer
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影响因子：
16.6
作者：
Elia I;Broekaert D;Christen S;Boon R;Radaelli E;Orth MF;Verfaillie C;Grünewald TGP;Fendt SM
通讯作者：
Fendt SM
影响因子：
11.4
作者：
Daneshmanesh, A. H.;Hojjat-Farsangi, M.;Mellstedt, H.
通讯作者：
Mellstedt, H.
影响因子：
10.5
作者：
D'Amico S;Shi J;Martin BL;Crawford HC;Petrenko O;Reich NC
通讯作者：
Reich NC
影响因子：
11.2
作者：
Ferrajoli, Alessandra;Faderl, Stefan;Estrov, Zeev
通讯作者：
Estrov, Zeev
影响因子：
3.9
作者：
An, Guohua;Wang, Xiaodong;Morris, Marilyn E.
通讯作者：
Morris, Marilyn E.