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Role of a transmembrane protein, epithelial membrane protein 1, in the pathogenesis of pancreatic ductal adenocarcinoma

Oncogene volume 45, pages 307–321 (2026)Cite this article

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Abstract

Pancreatic ductal adenocarcinoma (PDAC) has two subtypes: the “classical/progenitor” type and “basal-like/squamous” type, the latter of which has poor clinical outcomes with no effective treatment strategies. We aimed to elucidate the role of epithelial membrane protein 1 (EMP1) in PDAC and its potential as a therapeutic target, particularly in aggressive disease such as “basal-like/squamous” type of PDAC. We examined the association of EMP1 expression using patient-derived organoids (PDOs) of human PDAC, K-RASLSL-G12D, Trp 53LSL-R172H, and Pdx1-Cre recombinase mice, human PDAC cell lines, and publicly available clinical datasets. The functional roles of EMP1 were evaluated in vitro and in vivo through its knockout and stable overexpression. EMP1 knockout reduced proliferation, metastasis, and drug resistance, whereas overexpression enhanced malignant features. Transcriptomic analysis revealed that EMP1 promotes epithelial-mesenchymal transition (EMT), extracellular matrix remodeling, and the K-RAS signaling pathway. EMP1 expression is inversely implicated in the oxidative phosphorylation pathway, which is characteristic of the “classical/progenitor” type. Furthermore, integrated analysis revealed an association between EMP1 expression and ERK phosphorylation. EMP1 plays a crucial role in the pathogenesis of PDAC, as it contributes to the proliferative and metastatic characteristics of PDAC. This study suggests that EMP1 may be a potential therapeutic target gene for aggressive disease.

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Fig. 1: Transcriptome analysis identifies EMP1 as a candidate gene for DP-type organoids.
Fig. 2: Emp1 knockout suppresses cancer cell growth, migration, and invasion.
Fig. 3: Overexpression of Emp1 enhances cancer cell growth, migration, and invasion in mouse PDAC.
Fig. 4: Molecular features of Emp1 are consistent with subtype classification in mouse PDAC.
Fig. 5: Emp1 is associated with “basal-like” type characteristics, activation of p-ERK, and increased EMT-related gene expression.
Fig. 6: Molecular features of EMP1 are consistent with subtype classification in human PDAC.
Fig. 7: EMP1 enhanced cancer cell growth, migration, and invasion in human PDAC.
Fig. 8: Effect of EMP1 on human PDAC organoids.

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Data availability

All data pertaining to this study are accessible from the corresponding authors upon reasonable request.

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Funding

This study received partial funding from the Mochida Memorial Foundation for Medical and Pharmaceutical Research (GAKF800717), which awarded a grant to NF. This study was also supported by Nanken-Kyoten (Grant No. 2025-kokunai 37), Science Tokyo (awarded to YO). Additional support was received from the Daiwa Securities Foundation (GAKF800710), (awarded to NF), as well as KAKENHI grants from the Japan Society for the Promotion of Science (JSPS) and the Ministry of Education, Culture, Sports, Science, and Technology of Japan, granted to AT (JP20K17023), YO (JP22H04993), KU (JP23K15013), and K.T. (JP23K19514), and NF (JP25K11254).

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Author notes

  1. These authors contributed equally: Nao Fujimori, Yoshihiro Ogawa.

Authors and Affiliations

  1. Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

    Akihisa Ohno, Nao Fujimori, Kazuhide Matsumoto, Shojiro Haji, Ayumu Takeno, Akihiko Suenaga, Shotaro Kakehashi, Takahiro Ueda, Masatoshi Murakami, Katsuhito Teramatsu, Keijiro Ueda, Takamasa Oono & Yoshihiro Ogawa

  2. Anticancer Strategies Laboratory, Institute of Science Tokyo, Tokyo, Japan

    Osamu Sugahara & Keiichi I. Nakayama

  3. Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

    Takeo Yamamoto & Yoshinao Oda

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  1. Akihisa Ohno
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  2. Nao Fujimori
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  3. Kazuhide Matsumoto
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Contributions

AO collected and curated the data, designed the study methodology, was involved with the provision of study materials and the preparation of the data presentation, conceptualized the study, analyzed and validated the data, wrote the original draft of the manuscript, and contributed to reviewing and editing the manuscript. NF supervised the experiment, acquired funding, and reviewed and edited the manuscript. KM developed the study methodology, curated the data, and was involved with the provision of study materials. OS developed the study methodology, curated the data, and was involved with the provision of study materials. AT developed the study methodology, acquired funding, and was involved with the provision of study materials. TY was involved in the provision of study materials. AS was also involved in the provision of study materials. SK developed the study methodology, curated the data, and was involved with the provision of study materials. TU was involved with the provision of study materials. MM was involved with the provision of study materials. KT acquired funding and was involved with the provision of study materials. KU acquired funding and was involved with the provision of study materials. TO developed the study methodology and was involved with the provision of study materials. SH developed the study methodology and contributed to the review and editing of the manuscript. Yoshinao Oda was instrumental in developing the study methodology and providing study materials. KIN developed the study methodology and was involved with the provision of study materials. Yoshihiro Ogawa supervised the experiment, acquired funding, and reviewed and edited the manuscript.

Corresponding authors

Correspondence to Nao Fujimori or Yoshihiro Ogawa.

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The authors declare no competing interests.

Ethics approval and consent to participate

The clinical data, tumor samples, and PDOs from consecutive cases of PDAC were prospectively obtained at Kyushu University Hospital between April 2023 and March 2024. This study followed the ethical standards of the 1964 Declaration of Helsinki and received approval from the Ethics Committee of Kyushu University Hospital (Approval no. 22121-02 and 22161-01). All participants provided written informed consent.

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Ohno, A., Fujimori, N., Matsumoto, K. et al. Role of a transmembrane protein, epithelial membrane protein 1, in the pathogenesis of pancreatic ductal adenocarcinoma. Oncogene 45, 307–321 (2026). https://doi.org/10.1038/s41388-025-03633-4

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