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Genetics and Genomics

Single-cell sequencing of PIT1-positive pituitary adenoma highlights the pro-tumour microenvironment mediated by IFN-γ-induced tumour-associated fibroblasts remodelling

British Journal of Cancer volume 128, pages 1117–1133 (2023)Cite this article

Subjects

Abstract

Background

PIT1-positive pituitary adenoma (PIT1-PA) is one of the most important lineages of pituitary adenoma (PA), which causes systematic endocrine disorders and a worse prognosis. Tumour-associated fibroblast (TAF) is a crucial stroma cell type in the tumour microenvironment (TME). However, cellular and functional heterogeneity of TAF and immune cells in PIT1-PA have not been fully investigated.

Methods

By single-cell RNA sequencing of four PIT1-PAs and further analyses, we characterised the molecular and functional profiles of 28 different cell subtypes.

Results

PA stem cells in PIT1/SF1-positve PA were in a hybrid epithelial/mesenchymal state, and differentiated along the PIT1- and SF- dependent branches. C1Q was overwhelmingly expressed in tumour-associated macrophages, indicating its pro-tumoral functionality. PIT1-PA progression was characterised by lower cell–cell communication strength and higher cell adhesion-associated signals, indicating the immunosuppressive but pro-invasive microenvironment. IFN-γ signal repressed functional remodelling of myofibroblastic TAF (mTAF) towards inflammatory TAF/antigen-presenting TAF. IFN-γ inhibited mTAF phenotypes and N-cadherin expression through STAT3 signal axis. CDH2 knockdown in TAFs abrogated their pro-tumour function in PAs.

Conclusions

Our study builds up a cellular landscape of PIT1-PA TME and highlights anti-tumour function of IFN-γ mediated TAF remodelling, which benefits clinical treatments and drug development.

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Fig. 1: Cell-type identification in PIT1-PA and subtype-specific oncogene analyses for epithelial.
Fig. 2: Diversity of hybrid epithelial/mesenchymal state of PIT1-PA tumour stem cells.
Fig. 3: Pseudotime differentiation trajectories of plurihormonal PIT1/SF1-positive PA.
Fig. 4: Molecular and functional heterogeneity of myeloid cells in PIT1-Pas.
Fig. 5: Characteristics of tumour-infiltrating lymphocytes.
Fig. 6: Cellular and functional remodelling of TAFs in PIT1-Pas.
Fig. 7: Cell–cell communication network and progression-associated alterations among TME in PIT1-Pas.
Fig. 8: IFN-γ inhibited PA progression via CDH2 suppression in TAFs.

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Data availability

The single-cell RNA sequencing data generated in this paper are available in National Genomics Data Center by accession no. HRA003110 (https://ngdc.cncb.ac.cn/gsa-human/).

Code availability

R scripts used in this study to analyse data and generate figures can be found in Github (https://github.com/lvliang418/single-cell-RNAseq-for-PIT1-PA).

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Acknowledgements

We appreciated the kindly help from Dr. Tang Jie (West China Hospital of Sichuan University) for technical support in scRNA-seq experiments, and Prof. Lu Kefeng (West China Hospital of Sichuan University) for language editing. We also appreciated the help from Figdraw Group for providing images in Fig. 1a.

Funding

We appreciated the financial supports from the National Natural Science Foundation of China (Grants No. 82072582), Sichuan Science and Technology Program (Grants No. 2023NSFSC1869 and 2022YFS0322), Post-Doctor Research Project, West China Hospital, Sichuan University (Grants No. 2020HXBH157) and 1.3.5 project for disciplines of excellence, West China Hospital, Sichuan University (Grants No. 2019HXFH018).

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Authors and Affiliations

  1. Department of Neurosurgery, Pituitary Adenoma Multidisciplinary Center, West China Hospital of Sichuan University, Chengdu, China

    Liang Lyu, Yong Jiang, Weichao Ma, Haiyan Li, Ao Shen, Yang Yu, Shu Jiang, Peizhi Zhou & Senlin Yin

  2. State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Clinical Medical School, Sichuan University, Chengdu, China

    Liang Lyu, Haiyan Li & Huihui Li

  3. Department of Neurosurgery, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, China

    Yong Jiang & Weichao Ma

  4. Departments of Thoracic Oncology, West China Hospital of Sichuan University, Chengdu, Sichuan, China

    Xiaoling Liu

  5. Institute of Clinical Pathology, West China Hospital of Sichuan University, Chengdu, Sichuan, China

    Li Li

  6. Department of Pathology, West China Second University Hospital, Sichuan University, Chengdu, China

    Huihui Li

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Contributions

LL, SY, HL, SJ and PZ conceived the project. LL and SY wrote the manuscript with help from all authors. HL, XL and WM performed scRNA-seq. LL, HL and LL performed IF, IHC and imaging. LL conducted the bioinformatics analyses. LL and YJ performed cellular and molecular investigations. AS constructed some of the figures. All authors edited and proofread the manuscript.

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Correspondence to Huihui Li, Peizhi Zhou or Senlin Yin.

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All experimental procedures involved human tumour samples were approved by the Institutional Review Board of West China Hospital of Sichuan University. Signed informed consents were obtain from patients before surgery. The animal experiments were performed according to the Guidelines set forth by Chinese National Institutes of Health and institutional guidelines and approved by the Biomedical Research Ethics Committee of West China Hospital of Sichuan University.

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Lyu, L., Jiang, Y., Ma, W. et al. Single-cell sequencing of PIT1-positive pituitary adenoma highlights the pro-tumour microenvironment mediated by IFN-γ-induced tumour-associated fibroblasts remodelling. Br J Cancer 128, 1117–1133 (2023). https://doi.org/10.1038/s41416-022-02126-5

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