mTOR inhibition suppresses Myc-driven polyposis by inducing immunogenic cell death

Area of Science:

• Oncology
• Molecular Biology
• Immunology

Background:

• Myc is a critical driver in colorectal cancer (CRC) development and progression.
• Targeting Myc remains a significant challenge in CRC therapy.

Purpose of the Study:

• To investigate the efficacy of mTOR inhibition in suppressing intestinal polyp formation and progression in a mouse model of CRC.
• To elucidate the molecular mechanisms underlying the anti-tumorigenic effects of mTOR inhibition, focusing on Myc regulation, apoptosis, and immune response.

Main Methods:

• Treatment of APC^Min/+ mice with Everolimus (an mTOR inhibitor) in their diet.
• Analysis of polyp formation, regression, lifespan, and molecular markers (p-4EBP1, p-S6, Myc, p-S552 β-catenin).
• Assessment of apoptosis, ER stress, immune cell infiltration (innate and T-cells), and validation in human colonic cells and specific knockout mouse models (EIF4E S209A, BID).

Main Results:

• Everolimus treatment potently suppressed intestinal polyp formation, regressed established polyps, and prolonged lifespan in APC^Min/+ mice.
• Inhibition reduced key signaling proteins (p-4EBP1, p-S6, Myc) and induced apoptosis in polyp cells.
• Apoptosis was linked to ER stress, extrinsic pathway activation, and subsequent recruitment of innate and T-cells, effects not observed in normal intestinal crypts.
• Myc-dependent induction of ER stress and apoptosis was crucial for Everolimus's anti-tumor efficacy and immune response.

Conclusions:

• mTOR and deregulated Myc represent a selective vulnerability in APC-driven intestinal tumorigenesis.
• Inhibition of mTOR disrupts metabolic and immune adaptation within tumors.
• This strategy reactivates immune surveillance, offering a potential pathway for long-term tumor control in colorectal cancer.