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Periostin secreted by cancer-associated fibroblasts promotes cancer progression and drug resistance in non-small cell lung cancer

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A Correction to this article was published on 18 December 2023

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Abstract

Cancer-associated fibroblasts (CAFs) are important components in the tumor microenvironment, and we sought to identify effective therapeutic targets in CAFs for non-small cell lung cancer (NSCLC). In this study, we established fibroblast cell lines from the cancerous and non-cancerous parts of surgical lung specimens from patients with NSCLC and evaluated the differences in behaviors towards NSCLC cells. RNA sequencing analysis was performed to investigate the differentially expressed genes between normal fibroblasts (NFs) and CAFs, and we identified that the expression of periostin (POSTN), which is known to be overexpressed in various solid tumors and promote cancer progression, was significantly higher in CAFs than in NFs. POSTN increased cell proliferation via NSCLC cells’ ERK pathway activation and induced epithelial-mesenchymal transition (EMT), which improved migration in vitro. In addition, POSTN knockdown in CAFs suppressed these effects, and in vivo experiments demonstrated that the POSTN knockdown improved the sensitivity of EGFR-mutant NSCLC cells for osimertinib treatment. Collectively, our results showed that CAF-derived POSTN is involved in tumor growth, migration, EMT induction, and drug resistance in NSCLC. Targeting CAF-secreted POSTN could be a potential therapeutic strategy for NSCLC.

Key messages

• POSTN is significantly upregulated in CAFs compared to normal fibroblasts in NCSLC.

• POSTN increases cell proliferation via activation of the NSCLC cells’ ERK pathway.

• POSTN induces EMT in NSCLC cells and improves the migration ability.

• POSTN knockdown improves the sensitivity for osimertinib in EGFR-mutant NSCLC cells.

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Data availability

The raw RNA-seq data generated in this study are publicly available in Gene Expression Omnibus (GEO) at GSE205814. Data sources and handling of publicly available data are described in the Materials and Methods. Further information is available from the corresponding author upon request.

Change history

Abbreviations

αSMA:

Alpha-smooth muscle actin

CAF:

Cancer-associated fibroblasts

FAP:

Fibroblast activation protein

GAPDH:

Glyceraldehyde-3-phosphate dehydrogenase

EMT:

Epithelial-mesenchymal transition

MAPK:

Mitogen-activated protein kinase

NF:

Normal fibroblasts

NSCLC:

Non-small cell lung cancer

POSTN:

Periostin

TME:

Tumor microenvironment

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Acknowledgements

The authors thank Ms. Fumiko Isobe for her technical assistance.

Funding

This study was supported by a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (Grant number 22529148).

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Authors and Affiliations

  1. Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan

    Fumiaki Takatsu, Ken Suzawa, Yin Min Thu, Masayoshi Ohki, Shimpei Tsudaka, Keiichi Date, Naoki Matsuda, Kazuma Iwata, Yidan Zhu, Kentaro Nakata, Kazuhiko Shien, Hiromasa Yamamoto, Mikio Okazaki, Seiichiro Sugimoto & Shinichi Toyooka

  2. Center for Comprehensive Genomic Medicine, Okayama University Hospital, Okayama, Japan

    Shuta Tomida

  3. Department of Cell Biology, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Okayama, Japan

    Masakiyo Sakaguchi

  4. Department of Pathology, Okayama University Hospital, Okayama, Japan

    Tomohiro Toji

  5. Department of Pharmacology, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany

    Akiko Nakayama

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  1. Fumiaki Takatsu
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Contributions

Conception and design: F. Takatsu, K. Suzawa, S. Tomida, M. Sakaguchi, and S. Toyooka. Acquisition of data: F. Takatsu, S. Tomida, and Y. Thu. Analysis and interpretation of data: F. Takatsu, K. Suzawa, S. Tomida, M. Sakaguchi, T. Toji, M. Ohki, S. Tsudaka, K. Date, N. Matsuda, K. Iwata, Y. Zhu, K. Nakata, K. Shien, H. Yamamoto, A. Nakayama, M. Okazaki, S. Sugimoto, and S. Toyooka. Writing, review, and revision of the manuscript: F. Takatsu, K. Suzawa, S. Tomida, and S. Toyooka. All authors have read and approved the final manuscript.

Corresponding author

Correspondence to Ken Suzawa.

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Ethics approval

Studies using clinical specimens were approved by the Okayama Medical School and Hospital’s Research Ethics Committee (Approval Number: # 1906–033). The protocol for animal models was approved by the Animal Care and Use Committee of Okayama University (Okayama, Japan: permit number: OKU-2016398), and this study was carried out in accordance with the Guidelines of the Okayama University.

Consent to participate

Informed consent was obtained from all individual patients for the use of their materials.

Competing interests

Shinichi Toyooka received research funding from Eli Lilly Japan, Taiho (Japan) and Chugai (Japan), and lecture fees from Chugai. All other authors have no conflict of interest.

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Takatsu, F., Suzawa, K., Tomida, S. et al. Periostin secreted by cancer-associated fibroblasts promotes cancer progression and drug resistance in non-small cell lung cancer. J Mol Med 101, 1603–1614 (2023). https://doi.org/10.1007/s00109-023-02384-7

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