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/).
-
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.
Metrics
-
- 1,068
- views
-
- 191
- downloads
-
- 7
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
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
-
- Cancer Biology
Metastasis is the leading cause of cancer-related mortality. Paneth cells provide stem cell niche factors in homeostatic conditions, but the underlying mechanisms of cancer stem cell niche development are unclear. Here, we report that Dickkopf-2 (DKK2) is essential for the generation of cancer cells with Paneth cell properties during colon cancer metastasis. Splenic injection of Dkk2 knockout (KO) cancer organoids into C57BL/6 mice resulted in a significant reduction of liver metastases. Transcriptome analysis showed reduction of Paneth cell markers such as lysozymes in KO organoids. Single-cell RNA sequencing analyses of murine metastasized colon cancer cells and patient samples identified the presence of lysozyme positive cells with Paneth cell properties including enhanced glycolysis. Further analyses of transcriptome and chromatin accessibility suggested hepatocyte nuclear factor 4 alpha (HNF4A) as a downstream target of DKK2. Chromatin immunoprecipitation followed by sequencing analysis revealed that HNF4A binds to the promoter region of Sox9, a well-known transcription factor for Paneth cell differentiation. In the liver metastatic foci, DKK2 knockout rescued HNF4A protein levels followed by reduction of lysozyme positive cancer cells. Taken together, DKK2-mediated reduction of HNF4A protein promotes the generation of lysozyme positive cancer cells with Paneth cell properties in the metastasized colon cancers.
-
- Cancer Biology
A high density of tumor-associated macrophages (TAMs) is associated with poorer prognosis and survival in breast cancer patients. Recent studies have shown that lipid accumulation in TAMs can promote tumor growth and metastasis in various models. However, the specific molecular mechanisms that drive lipid accumulation and tumor progression in TAMs remain largely unknown. Herein, we demonstrated that unsaturated fatty acids (FAs), unlike saturated ones, are more likely to form lipid droplets in murine macrophages. Specifically, unsaturated FAs, including linoleic acids (LA), activate the FABP4/CEBPα pathway, leading to triglyceride synthesis and lipid droplet formation. Furthermore, FABP4 enhances lipolysis and FA utilization by breast cancer cell lines, which promotes cancer cell migration in vitro and metastasis in vivo. Notably, a deficiency of FABP4 in murine macrophages significantly reduces LA-induced lipid metabolism. Therefore, our findings suggest FABP4 as a crucial lipid messenger that facilitates unsaturated FA-mediated lipid accumulation and lipolysis in TAMs, thus contributing to the metastasis of breast cancer.
