Purinergic receptor P2RY14 cAMP signaling regulates Schwann cell precursor self-renewal, Schwann cell proliferation, and nerve tumor initiation in a mouse model of neurofibromatosis
- University of Cincinnati, United States
- Cincinnati Children's Hospital Medical Center, United States
- High Point University, United States
- Mayo Clinic, United States
Abstract
Neurofibromatosis type 1 (NF1) is characterized by nerve tumors called neurofibromas, in which Schwann cells (SCs) show deregulated RAS signaling. NF1 is also implicated in regulation of cAMP. We identified the G-protein-coupled receptor (GPCR) P2RY14 in human neurofibromas, neurofibroma-derived SC precursors (SCPs), mature SCs and mouse SCPs. Mouse Nf1-/-SCP self-renewal was reduced by genetic or pharmacological inhibition of P2RY14. In a mouse model of NF1, genetic deletion of P2RY14 rescued low cAMP signaling, increased mouse survival, delayed neurofibroma initiation, and improved SC Remak bundles. P2RY14 signals via Gi to increase intracellular cAMP, implicating P2RY14 as a key upstream regulator of cAMP. We found that elevation of cAMP by either blocking the degradation of cAMP or by using a P2RY14 inhibitor diminished NF1-/-SCP self-renewal in vitro and neurofibroma SC proliferation in in vivo. These studies identifyP2RY14 as a critical regulator of SCP self-renewal, SC proliferation and neurofibroma initiation.
Data availability
The data sets and original figures generated during this study will be available at Synapse Project (https://www.synapse.org/).
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Understanding the role of purinergic signaling on tumor formation in a mouse model of Nf1Synapse, doi.org/10.7303/syn27752640.
Article and author information
Author details
Jennifer Patritti Cram
Funding
National Institutes of Health (T32-NS007453)
- Jennifer Patritti Cram
Children's Tumor Foundation Younf Investigator Award
- Jennifer Patritti Cram
National Institutes of Health (NIH-R01-NS28840)
- Nancy Ratner
National Institutes of Health (NIH-R37-NS083580)
- Nancy Ratner
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (#2018-0103 expiration 01-2022) of Cincinnati Children's Hospital. The protocol was approved by the Committee on the Ethics of Animal Experiments of the Cincinnati Children's Hospital.
Copyright
© 2022, Patritti Cram et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Purinergic receptor P2RY14 cAMP signaling regulates Schwann cell precursor self-renewal, Schwann cell proliferation, and nerve tumor initiation in a mouse model of neurofibromatosis
eLife 11:e73511.
https://doi.org/10.7554/eLife.73511
Further reading
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Background:
Cervical adenocarcinoma (ADC) is more aggressive compared to other types of cervical cancer (CC), such as squamous cell carcinoma (SCC). The tumor immune microenvironment (TIME) and tumor heterogeneity are recognized as pivotal factors in cancer progression and therapy. However, the disparities in TIME and heterogeneity between ADC and SCC are poorly understood.
Methods:
We performed single-cell RNA sequencing on 11 samples of ADC tumor tissues, with other 4 SCC samples served as controls. The immunochemistry and multiplexed immunofluorescence were conducted to validate our findings.
Results:
Compared to SCC, ADC exhibited unique enrichments in several sub-clusters of epithelial cells with elevated stemness and hyper-malignant features, including the Epi_10_CYSTM1 cluster. ADC displayed a highly immunosuppressive environment characterized by the enrichment of regulatory T cells (Tregs) and tumor-promoting neutrophils. The Epi_10_CYSTM1 cluster recruits Tregs via ALCAM-CD6 signaling, while Tregs reciprocally induce stemness in the Epi_10_CYSTM1 cluster through TGFβ signaling. Importantly, our study revealed that the Epi_10_CYSTM1 cluster could serve as a valuable predictor of lymph node metastasis for CC patients.
Conclusions:
This study highlights the significance of ADC-specific cell clusters in establishing a highly immunosuppressive microenvironment, ultimately contributing to the heightened aggressiveness and poorer prognosis of ADC compared to SCC.
Funding:
Funded by the National Natural Science Foundation of China (82002753; 82072882; 81500475) and the Natural Science Foundation of Hunan Province (2021JJ40324; 2022JJ70103).
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