Integrated transcriptomics, proteomics and metabolomics-based analysis uncover TAM2-associated glycolysis and pyruvate metabolic remodeling in pancreatic cancer

Xin Li; Yan Du; Wenkai Jiang; Shi Dong; Wancheng Li; Huan Tang; Jianfeng Yi; Wence Zhou; Hui Zhang

doi:10.3389/fimmu.2023.1170223

Integrated transcriptomics, proteomics and metabolomics-based analysis uncover TAM2-associated glycolysis and pyruvate metabolic remodeling in pancreatic cancer

Front Immunol. 2023 Aug 17:14:1170223. doi: 10.3389/fimmu.2023.1170223. eCollection 2023.

Authors

Xin Li¹, Yan Du², Wenkai Jiang², Shi Dong², Wancheng Li², Huan Tang², Jianfeng Yi^{3

4}, Wence Zhou^{1

2}, Hui Zhang^{1

2}

Affiliations

¹ Department of General Surgery, Lanzhou University Second Hospital, Lanzhou, China.
² The Second School of Clinical Medicine, Lanzhou University, Lanzhou, China.
³ Department of General Surgery, The First School of Clinical Medicine of Lanzhou University, Lanzhou, China.
⁴ Department of Surgery, The First School of Clinical Medicine of Gansu University of Chinese Medicine, Lanzhou, China.

Abstract

Introduction: Tumor-associated macrophage 2 (TAM2) abundantly infiltrates pancreatic ductal adenocarcinoma (PAAD), and its interaction with malignant cells is involved in the regulation of tumor metabolism. In this study, we explored the metabolic heterogeneity involved in TAM2 by constructing TAM2-associated metabolic subtypes in PAAD.

Materials and methods: PAAD samples were classified into molecular subtypes with different metabolic characteristics based on a multi-omics analysis strategy. 20 PAAD tissues and 10 normal pancreatic tissues were collected for proteomic and metabolomic analyses. RNA sequencing data from the TCGA-PAAD cohort were used for transcriptomic analyses. Immunohistochemistry was used to assess TAM2 infiltration in PAAD tissues.

Results: The results of transcriptomics and immunohistochemistry showed that TAM2 infiltration levels were upregulated in PAAD and were associated with poor patient prognosis. The results of proteomics and metabolomics indicated that multiple metabolic processes were aberrantly regulated in PAAD and that this dysregulation was linked to the level of TAM2 infiltration. WGCNA confirmed pyruvate and glycolysis/gluconeogenesis as co-expressed metabolic pathways of TAM2 in PAAD. Based on transcriptomic data, we classified the PAAD samples into four TAM2-associated metabolic subtypes (quiescent, pyruvate, glycolysis/gluconeogenesis and mixed). Metabolic subtypes were each characterized in terms of clinical prognosis, tumor microenvironment, immune cell infiltration, chemotherapeutic drug sensitivity, and functional mechanisms.

Conclusion: Our study confirmed that the metabolic remodeling of pyruvate and glycolysis/gluconeogenesis in PAAD was closely related to TAM2. Molecular subtypes based on TAM2-associated metabolic pathways provided new insights into prognosis prediction and therapy for PAAD patients.

Keywords: glycolysis; metabolic classification; pancreatic cancer; pyruvate; tumor-associated macrophage 2.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Carcinoma, Pancreatic Ductal* / genetics
Glycolysis
Humans
Metabolomics
Pancreatic Neoplasms* / genetics
Proteomics
Pyruvic Acid
Transcriptome
Tumor Microenvironment

Substances

Pyruvic Acid

Grants and funding

The study was funded by the (1) National Natural Science Foundation of China (grant number 82260555); (2) Medical Innovation and Development Project of Lanzhou University (grant number lzuyxcx-2022-177); (3) Major Science and Technology Projects of Gansu Province (grant number 22ZD6FA021-4); (4) Lanzhou Science and Technology Plan Project (grant number 2020-ZD-60); (5) Open Project of Gansu Provincial Key Laboratory for Mining and Innovation Transformation of Traditional Chinese Medicine (grant number ZYZX-2020-08).