# Clinical significance and mechanism of action of exosomal microRNAs in Neuroblastoma chemoresistance.

> **NIH NIH R01** · UNIVERSITY OF HAWAII AT MANOA · 2021 · $316,635

## Abstract

Neuroblastoma (NB) is the most common solid cancer in children outside of the skull and it still kills about 40%
of patients. There is increasing evidence that the tumor microenvironment promotes resistance of NB to
chemotherapy. In particular, Tumor-Associated Macrophages (TAMs) promote NB growth and resistance.
However, there are two fundamental gaps in our knowledge of this interaction: 1) We do not know which
molecular mechanisms mediate TAM pro-tumoral effects and consequently we are unable to exploit such
mechanisms for new therapeutic purposes; 2) We have not identified a “systemic” parameter that reflects the
degree of TAM infiltration in the primary tumor, and consequently we cannot identify which subsets of patients
would particularly benefit from an anti-TAM therapy.
Our preliminary data support a role for microRNAs (miRs) within exosomes as responsible for the increased
NB proliferation and drug resistance through the direct targeting of TP53, the most frequently dys-regulated
gene in human cancers and with a well established role in multi-drug resistance in NB. Specifically, NB cells
secrete exosomal miR-21, which is up-taken by surrounding macrophages and can bind to Toll-like receptor 8
(TLR8), triggering TLR8 activation in macrophages. As a consequence of this activation, we showed up-
regulation of miR-155, -487a and -597, all predicted to target TP53. We also engineered a nanoparticle coated
with anti-CD163 antibody to specifically silence miR-155 in TAMs (that are CD163+). Finally, we were able to
develop a modified protocol that successfully isolates purer exosomes (meaning with lower protein
contaminants) both from cell supernatants and from patients’ plasma. With this protocol we isolated CD163+
exosomes (released by TAMs) from the plasma of NB patients and healthy donors, and showed increased
levels of exosomal miR-155 in the plasma of NB patients compared to healthy donors. Therefore, we
hypothesize that NB cells, by secreting exosomal miR-21 that binds to TLR8 in surrounding TAMs, induce the
secretion of exosomal miR-155, -487a and -597 by TAMs and these miRs are transferred back to NB cells,
where they silence TP53 and increase NB multi-drug resistance. We also hypothesize that targeting these
miRs will restore sensitivity to chemotherapy. Finally, we believe that the levels of TAM-derived exosomal miRs
will reflect the degree of TAM infiltration in the primary tumor and will correlate with clinical outcome measures.
We will investigate these hypotheses in 3 specific aims: 1) a study of the mechanisms by which exosomal
miRs induce resistance to therapy in NB; 2) an assessment of the therapeutic potential of targeting NB and
TAM-derived exosomal miRs to overcome NB resistance; 3) a determination of TAM-derived exosomal miRs
as indicators of TAM-infiltration in the primary tumor and of clinical outcome measures. The successful
completion of this research will identify new molecular targets for NB, identify subsets of patie...

## Key facts

- **NIH application ID:** 10073481
- **Project number:** 5R01CA219024-05
- **Recipient organization:** UNIVERSITY OF HAWAII AT MANOA
- **Principal Investigator:** Muller Fabbri
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $316,635
- **Award type:** 5
- **Project period:** 2018-01-01 → 2021-06-27

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10073481

## Citation

> US National Institutes of Health, RePORTER application 10073481, Clinical significance and mechanism of action of exosomal microRNAs in Neuroblastoma chemoresistance. (5R01CA219024-05). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10073481. Licensed CC0.

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