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Theranostics 2022; 12(7):3104-3130. doi:10.7150/thno.69590 This issue Cite

Research Paper

Multi-scale integrative analyses identify THBS2+ cancer-associated fibroblasts as a key orchestrator promoting aggressiveness in early-stage lung adenocarcinoma

Haitang Yang1*, Beibei Sun2*, Liwen Fan1*, Wenyan Ma3*, Ke Xu1, Sean R. R. Hall4, Zhexin Wang1, Ralph A. Schmid5, Ren-Wang Peng5, Thomas M. Marti5, Wen Gao6, Jianlin Xu7✉, Weiwei Yang8✉, Feng Yao1✉

1. Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University; Shanghai, 200030, People's Republic of China.
2. Institute for Thoracic Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University; Shanghai, 200030, People's Republic of China.
3. Clinical Research Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, 200030, People's Republic of China.
4. Wyss Institute for Biologically Inspired Engineering, Harvard University; United States.
5. Division of General Thoracic Surgery, Department of BioMedical Research (DBMR), Inselspital, Bern University Hospital, University of Bern; Bern, 3010, Switzerland.
6. Department of Thoracic Surgery, Huadong Hospital Affiliated to FuDan University, China.
7. Department of Respiratory Medicine, Shanghai Chest Hospital, Jiao Tong University; Shanghai, 200030, People's Republic of China.
8. School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, People's Republic of China.
*These authors contributed equally to this work.

✉ Corresponding authors: Feng Yao (yaofengedu.cn), Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University; Shanghai, 200030, China. Tel. 021-222-00000; Fax. 021-222-00000; Weiwei Yang (wyangac.cn), School More

Citation:
Yang H, Sun B, Fan L, Ma W, Xu K, Hall SRR, Wang Z, Schmid RA, Peng RW, Marti TM, Gao W, Xu J, Yang W, Yao F. Multi-scale integrative analyses identify THBS2+ cancer-associated fibroblasts as a key orchestrator promoting aggressiveness in early-stage lung adenocarcinoma. Theranostics 2022; 12(7):3104-3130. doi:10.7150/thno.69590. https://www.thno.org/v12p3104.htm
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Abstract

Graphic abstract

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.

Keywords: early-stage lung adenocarcinoma, THBS2, exosome, cancer-associated fibroblast, immunotherapy

Citation styles

APA
Yang, H., Sun, B., Fan, L., Ma, W., Xu, K., Hall, S.R.R., Wang, Z., Schmid, R.A., Peng, R.W., Marti, T.M., Gao, W., Xu, J., Yang, W., Yao, F. (2022). Multi-scale integrative analyses identify THBS2+ cancer-associated fibroblasts as a key orchestrator promoting aggressiveness in early-stage lung adenocarcinoma. Theranostics, 12(7), 3104-3130. https://doi.org/10.7150/thno.69590.

ACS
Yang, H.; Sun, B.; Fan, L.; Ma, W.; Xu, K.; Hall, S.R.R.; Wang, Z.; Schmid, R.A.; Peng, R.W.; Marti, T.M.; Gao, W.; Xu, J.; Yang, W.; Yao, F. Multi-scale integrative analyses identify THBS2+ cancer-associated fibroblasts as a key orchestrator promoting aggressiveness in early-stage lung adenocarcinoma. Theranostics 2022, 12 (7), 3104-3130. DOI: 10.7150/thno.69590.

NLM
Yang H, Sun B, Fan L, Ma W, Xu K, Hall SRR, Wang Z, Schmid RA, Peng RW, Marti TM, Gao W, Xu J, Yang W, Yao F. Multi-scale integrative analyses identify THBS2+ cancer-associated fibroblasts as a key orchestrator promoting aggressiveness in early-stage lung adenocarcinoma. Theranostics 2022; 12(7):3104-3130. doi:10.7150/thno.69590. https://www.thno.org/v12p3104.htm

CSE
Yang H, Sun B, Fan L, Ma W, Xu K, Hall SRR, Wang Z, Schmid RA, Peng RW, Marti TM, Gao W, Xu J, Yang W, Yao F. 2022. Multi-scale integrative analyses identify THBS2+ cancer-associated fibroblasts as a key orchestrator promoting aggressiveness in early-stage lung adenocarcinoma. Theranostics. 12(7):3104-3130.

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