Multi-scale integrative analyses identify THBS2(+) cancer-associated fibroblasts as a key orchestrator promoting aggressiveness in early-stage lung adenocarcinoma.
Multi-scale integrative analyses identify THBS2(+) cancer-associated fibroblasts as a key orchestrator promoting aggressiveness in early-stage lung adenocarcinoma.
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DOI：
10.7150/thno.69590
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发表时间：
2022
期刊：
影响因子：
12.4
通讯作者：
Yao, Feng
中科院分区：
文献类型：
--
作者：
Yang, Haitang;Sun, Beibei;Fan, Liwen;Ma, Wenyan;Xu, Ke;Hall, Sean R. R.;Wang, Zhexin;Schmid, Ralph A.;Peng, Ren-Wang;Marti, Thomas M.;Gao, Wen;Xu, Jianlin;Yang, Weiwei;Yao, Feng
依据：早期肺腺癌（LUAD）患者亚组在根治性手术后的术后病程较差。然而，生物标志物分层这一高风险的子集和分子基础的侵略性表型仍然不清楚。研究方法：我们整合了大量和单细胞转录组学，蛋白质组学，分泌组学和临床早期LUAD样本的空间分析，以确定促进侵袭性表型的分子基础。结果如下：我们在多组学水平上鉴定并验证了THBS 2作为一种与肿瘤大小无关的生物标志物，可在早期LUAD的多个独立临床队列中稳健地预测术后生存率。此外，scRNA-seq数据显示，THBS 2仅来源于特定的癌症相关成纤维细胞（CAF）亚群，该亚群与经典标志物定义的CAF不同。有趣的是，我们的数据表明，THBS 2在早期LUAD肿瘤中优先通过外泌体分泌，具有高侵袭性，其在外周血浆中的水平与短期无复发生存期相关。进一步表征显示THBS 2-高早期LUAD的特征在于抑制的抗肿瘤免疫。除肿瘤细胞外，THBS 2 + CAFs主要与B和CD 8 + T淋巴细胞以及早期LUAD肿瘤微环境中的巨噬细胞相互作用，THBS 2-high LUAD与免疫细胞浸润减少但免疫耗竭标志物增加相关。临床上，THBS 2高表达预示着对免疫治疗的反应差和患者治疗后生存期短。最后，THBS 2重组蛋白抑制离体T细胞增殖并促进体内LUAD肿瘤生长和远处微转移。结论：我们的多水平分析揭示了肿瘤特异性THBS 2 + CAF是促进早期LUAD侵袭性的关键协调者。
Rationale: Subsets of patients with early-stage lung adenocarcinoma (LUAD) have a poor post-surgical course after curative surgery. However, biomarkers stratifying this high-risk subset and molecular underpinnings underlying the aggressive phenotype remain unclear. Methods: We integrated bulk and single-cell transcriptomics, proteomics, secretome and spatial profiling of clinical early-stage LUAD samples to identify molecular underpinnings that promote the aggressive phenotype. Results: We identified and validated THBS2, at multi-omic levels, as a tumor size-independent biomarker that robustly predicted post-surgical survival in multiple independent clinical cohorts of early-stage LUAD. Furthermore, scRNA-seq data revealed that THBS2 is exclusively derived from a specific cancer-associated fibroblast (CAF) subset that is distinct from CAFs defined by classical markers. Interestingly, our data demonstrated that THBS2 was preferentially secreted via exosomes in early-stage LUAD tumors with high aggressiveness, and its levels in the peripheral plasma associated with short recurrence-free survival. Further characterization showed that THBS2-high early-stage LUAD was characterized by suppressed antitumor immunity. Specifically, beyond tumor cells, THBS2+ CAFs mainly interact with B and CD8+ T lymphocytes as well as macrophages within tumor microenvironment of early-stage LUAD, and THBS2-high LUAD was associated with decreased immune cell infiltrates but increased immune exhaustion marker. Clinically, high THBS2 expression predicted poor response to immunotherapies and short post-treatment survival of patients. Finally, THBS2 recombinant protein suppressed ex vivo T cells proliferation and promoted in vivo LUAD tumor growth and distant micro-metastasis. Conclusions: Our multi-level analyses uncovered tumor-specific THBS2+ CAFs as a key orchestrator promoting aggressiveness in early-stage LUAD.
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影响因子：
4.6
作者：
Bankhead P;Loughrey MB;Fernández JA;Dombrowski Y;McArt DG;Dunne PD;McQuaid S;Gray RT;Murray LJ;Coleman HG;James JA;Salto-Tellez M;Hamilton PW
通讯作者：
Hamilton PW
影响因子：
4.6
作者：
David, Elizabeth;Thall, Peter F.;Kalhor, Neda;Hofstetter, Wayne L.;Rice, David C.;Roth, Jack A.;Swisher, Stephen G.;Walsh, Garrett L.;Vaporciyan, Ara A.;Wei, Caimea;Mehran, Reza J.
通讯作者：
Mehran, Reza J.
影响因子：
64.5
作者：
Gillette, Michael A.;Satpathy, Shankha;Carr, Steven A.
通讯作者：
Carr, Steven A.
影响因子：
20.4
作者：
Goldstraw, Peter;Chansky, Kari;Bolejack, Vanessa
通讯作者：
Bolejack, Vanessa
影响因子：
50.3
作者：
Costa, Ana;Kieffer, Yann;Mechta-Grigoriou, Fatima
通讯作者：
Mechta-Grigoriou, Fatima