A Novel Therapeutic Target for Small-Cell Lung Cancer: Tumor-Associated Repair-like Schwann Cells

Shuhui Cao; Yue Wang; Yan Zhou; Yao Zhang; Xuxinyi Ling; Lincheng Zhang; Jingwen Li; Yu Yang; Weimin Wang; Michael R Shurin; Hua Zhong

doi:10.3390/cancers14246132

A Novel Therapeutic Target for Small-Cell Lung Cancer: Tumor-Associated Repair-like Schwann Cells

Cancers (Basel). 2022 Dec 12;14(24):6132. doi: 10.3390/cancers14246132.

Authors

Shuhui Cao¹, Yue Wang¹, Yan Zhou¹, Yao Zhang¹, Xuxinyi Ling¹, Lincheng Zhang¹, Jingwen Li¹, Yu Yang¹, Weimin Wang¹, Michael R Shurin^{2

3}, Hua Zhong¹

Affiliations

¹ Department of Pulmonary, Shanghai Chest Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China.
² Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA 15261, USA.
³ Department of Immunology, University of Pittsburgh Medical Center, Pittsburgh, PA 15261, USA.

Abstract

Small-cell lung cancer (SCLC), representing 15-20% of all lung cancers, is an aggressive malignancy with a distinct natural history, poor prognosis, and limited treatment options. We have previously identified Schwann cells (SCs), the main glial cells of the peripheral nervous system, in tumor tissues and demonstrated that they may support tumor spreading and metastasis formation in the in vitro and in vivo models. However, the role of SCs in the progression of SCLC has not been investigated. To clarify this issue, the cell proliferation assay, the annexin V apoptosis assay, and the transwell migration and invasion assay were conducted to elucidate the roles in SCLC of tumor-associated SCs (TA-SCs) in the proliferation, apoptosis, migration, and invasion of SCLC cells in vitro, compared to control group. In addition, the animal models to assess SC action's effects on SCLC in vivo were also developed. The result confirmed that TA-SCs have a well-established and significant role in facilitating SCLC cell cancer migration and invasion of SCLC in vitro, and we also observed that SC promotes tumor growth of SCLC in vivo and that TA-SCs exhibited an advantage and show a repair-like phenotype, which allowed defining them as tumor-associated repair SCs (TAR-SCs). Potential molecular mechanisms of pro-tumorigenic activity of TAR-SCs were investigated by the screening of differentially expressed genes and constructing networks of messenger-, micro-, and long- non-coding RNA (mRNA-miRNA-lncRNA) using DMS114 cells, a human SCLC, stimulated with media from DMS114-activated SCs, non-stimulated SCs, and appropriate controls. This study improves our understanding of how SCs, especially tumor-activated SCs, may promote SCLC progression. Our results highlight a new functional phenotype of SCs in cancer and bring new insights into the characterization of the nervous system-tumor crosstalk.

Keywords: Schwann cells; gene expression; miRNA; small-cell lung cancer; tumor progression.

Grants and funding

This work was supported by the Shanghai Committee of Science and Technology (Project No. 19411970900), the National Natural Science Foundation of China (Project Nos. 82072573 and 82002426), the Project of Science and Technology Development Fund of Shanghai Chest Hospital (Project No. 2021YNZYB02), and the Shanghai Sailing Program (Project No. 20YF1444600). These funders played no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.