UPP1 promotes lung adenocarcinoma progression through the induction of an immunosuppressive microenvironment

Yin Li, Manling Jiang, Ling Aye, Li Luo, Yong Zhang, Fengkai Xu, Yongqi Wei, Dan Peng, Xiang He, Jie Gu, Xiaofang Yu, Guoping Li (), Di Ge () and Chunlai Lu ()
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Yin Li: Fudan University
Manling Jiang: Affiliated Hospital of Southwest Jiaotong University, The Third People’s Hospital of Chengdu
Ling Aye: Fudan University
Li Luo: Affiliated Hospital of Southwest Jiaotong University, The Third People’s Hospital of Chengdu
Yong Zhang: Fudan University
Fengkai Xu: Fudan University
Yongqi Wei: Fudan University
Dan Peng: Affiliated Hospital of Southwest Jiaotong University, The Third People’s Hospital of Chengdu
Xiang He: Affiliated Hospital of Southwest Jiaotong University, The Third People’s Hospital of Chengdu
Jie Gu: Fudan University
Xiaofang Yu: Fudan University
Guoping Li: Affiliated Hospital of Southwest Jiaotong University, The Third People’s Hospital of Chengdu
Di Ge: Fudan University
Chunlai Lu: Fudan University

Nature Communications, 2024, vol. 15, issue 1, 1-23

Abstract: Abstract The complexity of the tumor microenvironment (TME) is a crucial factor in lung adenocarcinoma (LUAD) progression. To gain deeper insights into molecular mechanisms of LUAD, we perform an integrative single-cell RNA sequencing (scRNA-seq) data analysis of 377,574 cells from 117 LUAD patient samples. By linking scRNA-seq data with bulk gene expression data, we identify a cluster of prognostic-related UPP1high tumor cells. These cells, primarily situated at the invasive front of tumors, display a stronger association with the immunosuppressive components in the TME. Our cytokine array analysis reveals that the upregulation of UPP1 in tumor cells leads to the increased release of various immunosuppressive cytokines, with TGF-β1 being particularly prominent. Furthermore, this UPP1 upregulation also elevates the expression of PD-L1 through the PI3K/AKT/mTOR pathway, which contributes to the suppression of CD8 + T cells. Cytometry by time-of-flight (CyTOF) analysis provides additional evidence of the role of UPP1 in shaping the immunosuppressive nature of the TME. Using patient-derived organoids (PDOs), we discover that UPP1high tumors exhibit relatively increased sensitivity to Bosutinib and Dasatinib. Collectively, our study highlights the immunosuppressive role of UPP1 in LUAD, and these findings may provide insights into the molecular features of LUAD and facilitate the development of personalized treatment strategies.

Date: 2024
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DOI: 10.1038/s41467-024-45340-w

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