Targeting Cystine Addiction Suppresses Breast Cancer Lung Metastasis

Area of Science:

• Oncology
• Metabolic pathways
• Cancer metastasis

Background:

• Metastatic disease is a primary driver of cancer mortality.
• Metastasis involves metabolic adaptations enabling cancer cell survival in new microenvironments.
• Understanding these metabolic vulnerabilities can yield more effective anti-metastasis therapies.

Purpose of the Study:

• To investigate metabolic pathway alterations in breast cancer cells metastasizing to the lung.
• To identify metabolic dependencies unique to metastatic cells.

Main Methods:

• Utilized in vivo and ex vivo models of MYC-driven breast tumorigenesis.
• Employed stable isotope-resolved metabolomics, mass spectrometry imaging, and single-cell RNA sequencing.
• Analyzed metabolic changes during mammary gland tumor cell metastasis to the lung.

Main Results:

• Lung metastases showed increased glutathione synthesis, fueled by elevated cystine uptake.
• Metastatic cells demonstrated a dependency on extracellular cysteine/cystine.
• Downregulated intracellular cysteine synthesis via the transsulfuration pathway was observed in metastatic cells.

Conclusions:

• Targeting cystine/cysteine metabolism exploits a vulnerability specific to metastatic cells.
• Cyst(e)inase combined with radiotherapy effectively reduced lung metastatic burden.
• This strategy sensitizes metastatic cells to radiotherapy-induced oxidative stress, offering a promising targeted approach.