NDLI: MIF/CXCR4 signaling axis contributes to survival, invasion, and drug resistance of metastatic neuroblastoma cells in the bone marrow microenvironment

Content Provider	Springer Nature : BioMed Central
Author	Garcia-Gerique, Laura García, Marta Garrido-Garcia, Alícia Gómez-González, Soledad Torrebadell, Montserrat Prada, Estela Pascual-Pasto, Guillem Muñoz, Oscar Perez-Jaume, Sara Lemos, Isadora Salvador, Noelia Vila-Ubach, Monica Doncel-Requena, Ana Suñol, Mariona Carcaboso, Angel M. Mora, Jaume Lavarino, Cinzia
Abstract	Background The bone marrow (BM) is the most common site of dissemination in patients with aggressive, metastatic neuroblastoma (NB). However, the molecular mechanisms underlying the aggressive behavior of NB cells in the BM niche are still greatly unknown. In the present study, we explored biological mechanisms that play a critical role in NB cell survival and progression in the BM and investigated potential therapeutic targets. Methods Patient-derived bone marrow (BM) primary cultures were generated using fresh BM aspirates obtained from NB patients. NB cell lines were cultured in the presence of BM conditioned media containing cell-secreted factors, and under low oxygen levels (1% O2) to mimic specific features of the BM microenvironment of high-risk NB patients. The BM niche was explored using cytokine profiling assays, cell migration-invasion and viability assays, flow cytometry and analysis of RNA-sequencing data. Selective pharmacological inhibition of factors identified as potential mediators of NB progression within the BM niche was performed in vitro and in vivo. Results We identified macrophage migration inhibitory factor (MIF) as a key inflammatory cytokine involved in BM infiltration. Cytokine profiling and RNA-sequencing data analysis revealed NB cells as the main source of MIF in the BM, suggesting a potential role of MIF in tumor invasion. Exposure of NB cells to BM-conditions increased NB cell-surface expression of the MIF receptor CXCR4, which was associated with increased cell viability, enhanced migration-invasion, and activation of PI3K/AKT and MAPK/ERK signaling pathways. Moreover, subcutaneous co-injection of NB and BM cells enhanced tumor engraftment in mice. MIF inhibition with 4-IPP impaired in vitro NB aggressiveness, and improved drug response while delayed NB growth, improving survival of the NB xenograft model. Conclusions Our findings suggest that BM infiltration by NB cells may be mediated, in part, by MIF-CXCR4 signaling. We demonstrate the antitumor efficacy of MIF targeting in vitro and in vivo that could represent a novel therapeutic target for patients with disseminated high-risk NB.
Related Links	https://bmccancer.biomedcentral.com/counter/pdf/10.1186/s12885-022-09725-8.pdf
Ending Page	17
Page Count	17
Starting Page	1
File Format	HTM / HTML
ISSN	14712407
DOI	10.1186/s12885-022-09725-8
Journal	BMC Cancer
Issue Number	1
Volume Number	22
Language	English
Publisher	BioMed Central
Publisher Date	2022-06-17
Access Restriction	Open
Subject Keyword	Cancer Research Oncology Surgical Oncology Health Promotion and Disease Prevention Biomedicine Medicine Public Health Neuroblastoma Bone marrow MIF CXCR4 Hypoxia 4-IPP Medicine/Public Health
Content Type	Text
Resource Type	Article
Subject	Cancer Research Oncology Genetics
Journal Impact Factor	3.4/2023
5-Year Journal Impact Factor	3.8/2023

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1	Ministry of Education (GoI), Department of Higher Education	Sanctioning Authority	https://www.education.gov.in/ict-initiatives
2	Indian Institute of Technology Kharagpur	Host Institute of the Project: The host institute of the project is responsible for providing infrastructure support and hosting the project	https://www.iitkgp.ac.in
3	National Digital Library of India Office, Indian Institute of Technology Kharagpur	The administrative and infrastructural headquarters of the project	Dr. B. Sutradhar bsutra@ndl.gov.in
4	Project PI / Joint PI	Principal Investigator and Joint Principal Investigators of the project	Dr. B. Sutradhar bsutra@ndl.gov.in Prof. Saswat Chakrabarti will be added soon
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