Sung Hwan Lee1,2, Ho Kyoung Hwang3,4, Woo Jung Lee3,4, Chang Moo Kang5,6. 1. Department of Surgery, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Republic of Korea. 2. Laboratory of HBP Integrative Precision Oncology, CHA Bio Complex, CHA Health System, Seongnam, Republic of Korea. 3. Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Yonsei University College of Medicine, Seoul, Republic of Korea. 4. Pancreatobiliary Cancer Center, Yonsei Cancer Center, Severance Hospital, 50-1, Yonsei-ro, Seodaemun-gu, Seoul, Republic of Korea. 5. Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Yonsei University College of Medicine, Seoul, Republic of Korea. cmkang@yuhs.ac. 6. Pancreatobiliary Cancer Center, Yonsei Cancer Center, Severance Hospital, 50-1, Yonsei-ro, Seodaemun-gu, Seoul, Republic of Korea. cmkang@yuhs.ac.
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.
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.
Authors: Dimitri A Raptis; Patricia Sánchez-Velázquez; Nikolaos Machairas; Alain Sauvanet; Alexandra Rueda de Leon; Atsushi Oba; Bas Groot Koerkamp; Brendan Lovasik; Carlos Chan; Charles J Yeo; Claudio Bassi; Cristina R Ferrone; David Kooby; David Moskal; Domenico Tamburrino; Dong-Sup Yoon; Eduardo Barroso; Eduardo de Santibañes; Emanuele F Kauffmann; Emanuel Vigia; Fabien Robin; Fabio Casciani; Fernando Burdío; Giulio Belfiori; Giuseppe Malleo; Harish Lavu; Hermien Hartog; Ho Kyuong Hwang; Ho-Seong Han; Ignasi Poves; Ismael Domínguez Rosado; Joon-Seong Park; Keith D Lillemoe; Keith J Roberts; Laurent Sulpice; Marc G Besselink; Mahmoud Abuawwad; Marco Del Chiaro; Martin de Santibañes; Massimo Falconi; Mizelle D'Silva; Michael Silva; Mohammed Abu Hilal; Motaz Qadan; Naomi M Sell; Nassiba Beghdadi; Niccolò Napoli; Olivier R C Busch; Oscar Mazza; Paolo Muiesan; Philip C Müller; Reena Ravikumar; Richard Schulick; Sarah Powell-Brett; Syed Hussain Abbas; Tara M Mackay; Thomas F Stoop; Tom K Gallagher; Ugo Boggi; Casper van Eijck; Pierre-Alain Clavien; Kevin C P Conlon; Giuseppe Kito Fusai Journal: Ann Surg Date: 2020-11 Impact factor: 12.969