Tumour-specific proline vulnerability uncovered by differential ribosome codon reading

Area of Science:

• Oncology
• Metabolic Engineering
• Molecular Biology

Background:

• Cancer cells rely on specific amino acid metabolism for survival and proliferation.
• Current methods lack tailored systems for detecting tumor-specific amino acid restrictions.
• L-asparaginase therapy highlights the potential of targeting amino acid deprivation in cancer.

Purpose of the Study:

• To develop a novel method for sensing restrictive amino acids within tumors.
• To investigate amino acid dependencies in kidney and breast cancers.
• To identify potential vulnerabilities for targeted cancer therapies.

Main Methods:

• Utilized ribosome profiling to develop diricore, a differential ribosome measurement procedure.
• Validated diricore using metabolic inhibitors and nutrient deprivation assays.
• Applied diricore to kidney and breast cancer models, including in vivo studies.

Main Results:

• Diricore successfully detected asparagine restriction and compensatory asparagine synthetase (ASNS) upregulation.
• Identified proline restriction in kidney and breast cancers, linked to PYCR1 induction.
• Demonstrated that PYCR1 suppression or knockout impedes tumor growth under proline limitation.

Conclusions:

• Diricore is a functional tool for identifying tumor-specific amino acid deficiencies.
• Proline metabolism and PYCR1 represent a potential therapeutic vulnerability in certain cancers.
• This approach can reveal novel targets for cancer treatment by exploiting metabolic pathways.