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Cellular and Molecular Biology

Neoadjuvant therapy alters the collagen architecture of pancreatic cancer tissue via Ephrin-A5

British Journal of Cancer volume 126, pages 628–639 (2022)Cite this article

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Abstract

Background

The treatment of pancreatic cancer (PDAC) remains clinically challenging, and neoadjuvant therapy (NAT) offers down staging and improved surgical resectability. Abundant fibrous stroma is involved in malignant characteristic of PDAC. We aimed to investigate tissue remodelling, particularly the alteration of the collagen architecture of the PDAC microenvironment by NAT.

Methods

We analysed the alteration of collagen and gene expression profiles in PDAC tissues after NAT. Additionally, we examined the biological role of Ephrin-A5 using primary cultured cancer-associated fibroblasts (CAFs).

Results

The expression of type I, III, IV, and V collagen was reduced in PDAC tissues after effective NAT. The bioinformatics approach provided comprehensive insights into NAT-induced matrix remodelling, which showed Ephrin-A signalling as a likely pathway and Ephrin-A5 (encoded by EFNA5) as a crucial ligand. Effective NAT reduced the number of Ephrin-A5+ cells, which were mainly CAFs; this inversely correlated with the clinical tumour shrinkage rate. Experimental exposure to radiation and chemotherapeutic agents suppressed proliferation, EFNA5 expression, and collagen synthesis in CAFs. Forced EFNA5 expression altered CAF collagen gene profiles similar to those found in PDAC tissues after NAT.

Conclusion

These results suggest that effective NAT changes the extracellular matrix with collagen profiles through CAFs and their Ephrin-A5 expression.

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Fig. 1: Comparison of the collagen-expressed area in the four pancreatic conditions.
Fig. 2: Alteration of collagen gene expression following neoadjuvant therapy (NAT).
Fig. 3: Visualisation of expressional profile and signalling after neoadjuvant therapy (NAT).
Fig. 4: Neoadjuvant therapy (NAT) suppressed EFNA5 positive cells in PDAC tissues.
Fig. 5: Experimental exposure of cancer-associated fibroblasts (CAFs) to chemotherapeutic reagents or radiation.

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Data availability

The datasets used and analysed during the current study are available from the corresponding author upon reasonable request.

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Acknowledgements

We thank Ms. Sachiko Miura and Toshiko Sakaguchi for excellent techniques. We also thank Fumiyo Saito (Chemical Evaluation Research Institute, Tokyo, Japan) for bioinformatic analysis. The authors are grateful to the Mr. Naoki Kimoto, Mr. Koichiro Horiguchi, and Ms. Miyuki Kubokawa (Amelieff, Tokyo, Japan) to modify the software program, and Naoko Tominaga (Dnaform, Kanagawa, Japan) to extract CAGE data in this study. We are grateful to the National Cancer Center Biobank for the tissue samples used in this study.

Funding

This work was supported by JSPS KAKENHI [21K07139(NH), 18K16377(KN)], and AMED [21ck0106540(NH)].

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Authors and Affiliations

  1. Division of Molecular Pathology, National Cancer Center Research Institute, Tokyo, Japan

    Kosei Nakajima, Yoshinori Ino, Chie Naito, Mari Shimasaki, Utako Ishimoto, Toshimitsu Iwasaki, Noriteru Doi & Nobuyoshi Hiraoka

  2. Department of Analytical Pathology, National Cancer Center Research Institute, Tokyo, Japan

    Kosei Nakajima, Yoshinori Ino, Chie Naito, Mari Shimasaki, Utako Ishimoto, Toshimitsu Iwasaki, Noriteru Doi & Nobuyoshi Hiraoka

  3. Hepato-Biliary and Pancreatic Surgery Division, National Cancer Center Hospital, Tokyo, Japan

    Satoshi Nara, Toshimitsu Iwasaki, Minoru Esaki, Yoji Kishi & Kazuaki Shimada

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Contributions

Study concept and design; KN and NK, acquisition of data, analysis and interpretation of data; KN, YI, CN, SN, MS, UI, TI, ND and NH, drafting of the manuscript; KN, critical revision of the manuscript for important intellectual content; NH, obtained funding; KN and NH, technical or material support; ME, YK, KS and NH, study supervision; NH.

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Correspondence to Nobuyoshi Hiraoka.

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The authors declare no competing interests.

Ethics approval and consent to participate

This study was approved by the Institutional Review Board of the National Cancer Center, Japan (#2005-077 and #2016-006). Informed consent was obtained from all participants involved in the study, and all clinical investigations were conducted in line with the principles of the Declaration of Helsinki.

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There are no individual person’s data from all participants involved in the study.

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Nakajima, K., Ino, Y., Naito, C. et al. Neoadjuvant therapy alters the collagen architecture of pancreatic cancer tissue via Ephrin-A5. Br J Cancer 126, 628–639 (2022). https://doi.org/10.1038/s41416-021-01639-9

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