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Deciphering the mechanisms of neuroblastoma metastasis by multi-omics analysis
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[eng] Neuroblastoma (NB), a heterogeneous pediatric cancer originating from neural crest cells,
presents significant clinical challenges due to its high propensity for metastasis. Approximately
60% of patients show widespread disease at the initial diagnosis, with metastasis being the
primary cause of NB-related deaths. Understanding the molecular mechanisms underlying
metastasis is crucial for the development of targeted therapies for patients with high-risk NB.
The metastatic process involves complex interactions between tumor cells and their
surroundings, with the tumor microenvironment (TME) playing a key role. Current in vivo
models for NB metastasis have limitations, including incomplete replication of metastatic
stages and difficulties in tumor tracking and removal. To address these issues, we established
a spontaneous metastasis in vivo model, allowing surgical removal of the primary tumor,
ensuring animal survival, and enabling metastatic cells to colonize distant organs. Our primary
objective was to identify a metastatic signature by multi-omics analyses, comparing primary
tumors and metastatic masses from the in vivo model. Whole-genome expression analysis
revealed that the most differentially expressed genes (DEGs) were linked to lymphatic
metastasis. Data integration emphasized the crucial role of the tumor microenvironment (TME)
in NB metastasis, particularly the TGF-β signaling pathway, suggesting a potential interaction
between TME and NB mesenchymal (MSN) phenotype induction. Podoplanin (PDPN), a
transmembrane glycoprotein, has emerged as a metastatic marker for NB. It exhibited distinct
cellular localization in NB cells, with a prominent cytoplasmic location in metastasis. Notably,
the membrane localization of PDPN in NB cells was linked to higher lymph node infiltration
rates in NB patients. By generating NB stable cell lines overexpressing PDPN, we
demonstrated that elevated levels were correlated with increased metastatic potential. Since
PDPN expression is known to be induced by interactions with stromal and immune cells, we
confirmed that NB cells can promote the polarization of fibroblasts into cancer-associated
fibroblasts (CAFs) and that PDPN is induced in NB cells through interactions with CAFs,
suggesting a potential feedback loop. Furthermore, PDPN expression was also induced by
low oxygen conditions and cytokines exposure, confirming significant regulation by TME.
Notably, NB cells released PDPN via exosomes to facilitate the establishment of premetastatic
niches by inducing stromal cell polarization.
Altogether, our data provide further insight into the mechanisms underlying metastasis in NB
and identify a novel NB metastatic driver to target, crucial to improve patients' outcome.
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MARTÍN SERRANO, Jara. Deciphering the mechanisms of neuroblastoma metastasis by multi-omics analysis. [consulta: 31 de gener de 2026]. [Disponible a: https://hdl.handle.net/2445/217353]