Profiling the Surfaceome Identifies Therapeutic Targets for Cells with Hyperactive mTORC1 Signaling

Area of Science:

• Biochemistry
• Oncology
• Proteomics

Background:

• Aberrant mTORC1 signaling is a key driver in various cancers and human disorders.
• Pharmacological inhibition of mTORC1 often yields limited durable clinical responses, necessitating alternative therapeutic strategies.

Purpose of the Study:

• To identify cell surface proteins upregulated by mTORC1 signaling.
• To explore novel therapeutic strategies targeting the cell surface proteome in mTORC1-driven diseases.

Main Methods:

• Proteomics survey comparing surfaceome of Tsc1-/- and Tsc1+/+ mouse embryonic fibroblasts.
• Validation in multiple mouse and human cell lines.
• Functional studies involving genetic ablation and biochemical inhibition of identified proteases.

Main Results:

• Identified 59 proteins upregulated by mTORC1 signaling.
• Confirmed significant induction of neprilysin (NEP/CD10) and aminopeptidase N (APN/CD13) by mTORC1.
• Demonstrated that constitutive mTORC1 signaling sensitizes cells to NEP and APN targeting.

Conclusions:

• mTORC1 signaling significantly influences the cell surface proteome.
• Neprilysin (NEP) and aminopeptidase N (APN) are critical targets for therapeutic intervention in mTORC1-driven cancers.
• Targeting these surface proteases may offer novel strategies for durable clinical responses.