cPLA2 blockade attenuates S100A7-mediated breast tumorigenicity by inhibiting the immunosuppressive tumor microenvironment.
cPLA2 blockade attenuates S100A7-mediated breast tumorigenicity by inhibiting the immunosuppressive tumor microenvironment.
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CPLA2阻断通过抑制免疫抑制的肿瘤微环境来减弱S100A7介导的乳腺致瘤性。
DOI：
10.1186/s13046-021-02221-0
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发表时间：
2022-02-08
期刊：
影响因子：
--
通讯作者：
Ganju RK
中科院分区：
文献类型：
--
作者：
Mishra S;Charan M;Shukla RK;Agarwal P;Misri S;Verma AK;Ahirwar DK;Siddiqui J;Kaul K;Sahu N;Vyas K;Garg AA;Khan A;Miles WO;Song JW;Bhutani N;Ganju RK
炎症相关的乳腺肿瘤生长的分子机制研究甚少。S100 A7是一种促炎分子，已被证明可增强乳腺癌的生长和转移。然而，S100 A7介导的促进肿瘤生长和转移的分子机制尚不清楚。使用人乳腺癌组织和血浆样品来分析S100 A7、cPLA 2和PGE 2的表达。使用S100 A7过表达或下调的人转移性乳腺癌细胞来评估S100 A7介导的下游信号传导机制。使用双转基因mS 100 a7 a15过表达、TNBC C3（1）/Tag转基因和人源化患者来源的异种移植小鼠模型和cPLA 2抑制剂（AACOCF 3）来研究S100 A7/cPLA 2/PGE 2信号传导在肿瘤生长和转移中的作用。此外，采用高度先进的多重成像CODEX来描绘S100 A7/cPLA 2抑制对各种免疫细胞募集的影响。在这项研究中，我们发现S100 A7和cPLA 2高表达，并与乳腺癌患者的总生存率降低相关。进一步的机制研究表明，S100 A7/cPLA 2信号促进cPLA 2的表达，介导其致癌作用。cPLA 2的药理学抑制在多种临床前模型中抑制S100 A7介导的肿瘤生长和转移，包括转基因和人源化患者来源的异种移植（PDX）小鼠模型。cPLA 2信号传导的减弱减少了肿瘤微环境（TME）中S100 A7介导的免疫抑制性骨髓细胞的募集。有趣的是，我们发现S100 A7/cPLA 2轴通过增加前列腺素E2（PGE 2）来增强免疫抑制微环境。此外，基于成像的CO检测（CODEX）分析显示，cPLA 2抑制增加了TME中活化和增殖的CD 4+和CD 8 + T细胞的浸润。此外，恶性乳腺癌患者CD 163+肿瘤相关巨噬细胞与S100 A7和cPLA 2的表达呈正相关。我们的研究通过产生抑制细胞毒性T细胞浸润的免疫抑制性TME，提供了关于S100 A7/cPLA 2之间的串扰在增强乳腺肿瘤生长和转移中的新机制见解。此外，我们的研究表明，S100 A7/cPLA 2可用作新的预后标志物和cPLA 2抑制剂作为有前途的药物对S100 A7过表达的侵袭性乳腺癌。在线版本包含补充材料，可通过10.1186/s13046-021-02221-0获得。
Molecular mechanisms underlying inflammation-associated breast tumor growth are poorly studied. S100A7, a pro-inflammatory molecule has been shown to enhance breast cancer growth and metastasis. However, the S100A7-mediated molecular mechanisms in enhancing tumor growth and metastasis are unclear. Human breast cancer tissue and plasma samples were used to analyze the expression of S100A7, cPLA2, and PGE2. S100A7-overexpressing or downregulated human metastatic breast cancer cells were used to evaluate the S100A7-mediated downstream signaling mechanisms. Bi-transgenic mS100a7a15 overexpression, TNBC C3 (1)/Tag transgenic, and humanized patient-derived xenograft mouse models and cPLA2 inhibitor (AACOCF3) were used to investigate the role of S100A7/cPLA2/PGE2 signaling in tumor growth and metastasis. Additionally, CODEX, a highly advanced multiplexed imaging was employed to delineate the effects of S100A7/cPLA2 inhibition on the recruitment of various immune cells. In this study, we found that S100A7 and cPLA2 are highly expressed and correlate with decreased overall survival in breast cancer patients. Further mechanistic studies revealed that S100A7/RAGE signaling promotes the expression of cPLA2 to mediate its oncogenic effects. Pharmacological inhibition of cPLA2 suppressed S100A7-mediated tumor growth and metastasis in multiple pre-clinical models including transgenic and humanized patient-derived xenograft (PDX) mouse models. The attenuation of cPLA2 signaling reduced S100A7-mediated recruitment of immune-suppressive myeloid cells in the tumor microenvironment (TME). Interestingly, we discovered that the S100A7/cPLA2 axis enhances the immunosuppressive microenvironment by increasing prostaglandin E2 (PGE2). Furthermore, CO-Detection by indEXing (CODEX) imaging-based analyses revealed that cPLA2 inhibition increased the infiltration of activated and proliferating CD4+ and CD8+ T cells in the TME. In addition, CD163+ tumor associated-macrophages were positively associated with S100A7 and cPLA2 expression in malignant breast cancer patients. Our study provides new mechanistic insights on the cross-talk between S100A7/cPLA2 in enhancing breast tumor growth and metastasis by generating an immunosuppressive TME that inhibits the infiltration of cytotoxic T cells. Furthermore, our studies indicate that S100A7/cPLA2 could be used as novel prognostic marker and cPLA2 inhibitors as promising drugs against S100A7-overexpressing aggressive breast cancer. The online version contains supplementary material available at 10.1186/s13046-021-02221-0.
S100A7-下调抑制了乳腺癌细胞中表皮生长因子诱导的信号传导，并阻止破骨细胞的形成。
影响因子：
3.7
作者：
Paruchuri, Vikram;Prasad, Anil;McHugh, Kevin;Bhat, Hari K.;Polyak, Kornelia;Ganju, Ramesh K.
通讯作者：
Ganju, Ramesh K.
影响因子：
3
作者：
Hoenerhoff MJ;Shibata MA;Bode A;Green JE
通讯作者：
Green JE