Inhibiting CCR3 expands cancer stem cells via c-Myc-NTSR1 axis and associates with tumor innervation features

Area of Science:

• Oncology
• Cancer Biology
• Molecular Signaling

Background:

• Cancer stem cells (CSCs) contribute to tumor heterogeneity, therapy resistance, and relapse.
• Chemokines mediate cancer stemness through intercellular signaling within the tumor microenvironment.
• The specific role and clinical significance of CCR3 in distinct tumor subpopulations are not well understood.

Purpose of the Study:

• To investigate the function and clinical relevance of CCR3 in cancer stem cells (CSCs) and parental cancer cells.
• To elucidate the molecular mechanisms underlying CCR3's regulation of cancer stemness and tumor progression.
• To explore the potential of targeting CCR3, in combination with the c-Myc-NTSR1 axis, for cancer therapy.

Main Methods:

• Enrichment of CSCs using serum-free spheroid culture to generate spheroid-derived CSCs (SDCSCs).
• Comprehensive characterization of SDCSCs and parental cells, including proliferation, clonogenicity, invasion, chemo-drug resistance, and in vivo tumorigenicity.
• Transcriptomic analysis and validation using TCGA databases for clinical relevance.
• Investigation of signaling pathways, including c-Myc, KRAS, mTORC, and HIF, and the effect of CCR3 inhibition.

Main Results:

• CCR3 silencing enhanced self-renewal, stemness markers, chemoresistance, and tumorigenicity in SDCSCs.
• Conversely, CCR3 silencing inhibited proliferation, colony formation, and invasion in parental cancer cells.
• Transcriptomic analysis revealed distinct pro-tumoral and anti-tumoral profiles induced by CCR3 silencing in SDCSCs and parental cells, respectively, via differential regulation of oncogenic pathways.
• CCR3 silencing in SDCSCs promoted c-Myc nuclear expression and NTSR1 upregulation, enhancing cancer stemness, an effect reversed by a c-Myc inhibitor.
• Clinically, low CCR3 expression correlated with enhanced cell growth, suppressed immune surveillance, activated stemness signaling, and tumor innervation, predicting poor prognosis, especially when combined with high NTSR1 expression.

Conclusions:

• CCR3 inhibition elicits divergent functional and transcriptomic responses in distinct tumor subpopulations.
• CCR3 expression levels and associated stemness/innervation signatures are potential prognostic biomarkers.
• Combined targeting of CCR3 and the c-Myc-NTSR1 axis presents a promising therapeutic strategy for eliminating CSCs and overcoming treatment resistance.