Targeting Translation and the Cell Cycle Inversely Affects CTC Metabolism but Not Metastasis

Area of Science:

• Oncology
• Cancer Metastasis
• Molecular Biology

Background:

• Melanoma brain metastasis (MBM) is a significant cause of poor prognosis, often diagnosed posthumously.
• Circulating tumor cells (CTCs) are key drivers of metastatic spread.
• A previously identified CTC RPL/RPS gene signature is linked to MBM onset.

Purpose of the Study:

• To investigate if targeting ribogenesis can prevent MBM and metastasis in CTC-derived xenografts.
• To evaluate the efficacy of omacetaxine, a protein translation inhibitor, with or without palbociclib, a CDK4/CDK6 inhibitor, in MBM models.
• To characterize the metabolic plasticity of circulating neoplastic cells.

Main Methods:

• Treatment of MBM mouse models with omacetaxine and/or palbociclib.
• Monitoring of metastatic development using necropsies and IVIS imaging.
• RNA-sequencing of mouse-blood-derived CTCs and metabolic analyses (mitochondrial stress tests, RT-qPCR).

Main Results:

• Drug treatment significantly decreased MBM and extracranial metastasis in mice.
• RNA-Seq revealed downregulation of key RPL/RPS genes in CTCs post-treatment.
• Omacetaxine and palbociclib exhibited inverse effects on cellular metabolism, highlighting the importance of dual targeting.
• The study provides the first functional metabolic characterization of patient-derived circulating neoplastic cells.

Conclusions:

• Dual targeting of cell translation and proliferation is critical for suppressing the plasticity of metastasis-competent CTCs.
• Inhibiting ribogenesis and cell proliferation effectively reduces melanoma brain metastasis.
• The findings offer insights into metabolic vulnerabilities of CTCs and potential therapeutic strategies for MBM.