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MCT4 as a potential therapeutic target to augment gemcitabine chemosensitivity in resected pancreatic cancer

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Abstract

Background

Pancreatic cancer is a devastating disease with a high relapse rate, even in case of resectable pancreatic cancer. Here, we aimed to identify the prognostic significance and therapeutic options of metabolic subtypes of resectable pancreatic cancer.

Method

Transcriptomic data were obtained from the TCGA-PAAD cohort in the The Cancer Genome Atlas (TCGA) data portal (n = 182). After integrative analysis of transcriptomic data in the discovery cohort, immunohistochemical (IHC) staining was performed in an independent cohort (n = 51) to validate the molecules of interest. Experimental testing for the molecules of interest was performed in vitro using pancreatic cancer cell line models AsPC1, BxPC3, MIA PaCa-2 and PANC-1.

Results

Two subtypes showing distinct gene expression patterns in the TCGA-PAAD dataset were identified. Of these, the active glucose metabolism subtype showed a significantly lower survival rate related to relapse after surgical resection. The genes SLC2A1 (GLUT1) and SLC16A3 (MCT4) were highly enriched in this subtype. The validation cohort showed a high MCT4 staining and a high relapse rate (p = 0.01). Several molecular pathways associated with aggressive tumor biology, including cell cycle regulation and Myc and mTOR downstream signaling, were highly enriched in the active glucose metabolism subtype, as well as with distinct responses to immunotherapy. MCT4 inhibition suppressed the in vitro malignant characteristics of pancreatic cancer cells and showed a synergistic effect with gemcitabine treatment.

Conclusions

From our data we conclude that MCT4 may serve as a potential therapeutic target in resectable pancreatic cancer. The precision medicine strategy for resectable pancreatic cancer should be validated in a clinical setting with a prospective study design.

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Data availability

Transcriptome data used in this study are available via the The Cancer Genome Atlas (TCGA)-PAAD cohort (https://portal.gdc.cancer.gov/).

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Funding

This study was supported by a faculty research grant from the Yonsei University College of Medicine (6-2015-0053).

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Authors and Affiliations

  1. Department of Surgery, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Republic of Korea

    Sung Hwan Lee

  2. Laboratory of HBP Integrative Precision Oncology, CHA Bio Complex, CHA Health System, Seongnam, Republic of Korea

    Sung Hwan Lee

  3. Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Yonsei University College of Medicine, Seoul, Republic of Korea

    Ho Kyoung Hwang, Woo Jung Lee & Chang Moo Kang

  4. Pancreatobiliary Cancer Center, Yonsei Cancer Center, Severance Hospital, 50-1, Yonsei-ro, Seodaemun-gu, Seoul, Republic of Korea

    Ho Kyoung Hwang, Woo Jung Lee & Chang Moo Kang

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  1. Sung Hwan Lee
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Correspondence to Chang Moo Kang.

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Lee, S.H., Hwang, H.K., Lee, W.J. et al. MCT4 as a potential therapeutic target to augment gemcitabine chemosensitivity in resected pancreatic cancer. Cell Oncol. 44, 1363–1371 (2021). https://doi.org/10.1007/s13402-021-00643-8

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