Dysregulated mTORC1 renders cells critically dependent on desaturated lipids for survival under tumor-like stress

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Solid tumors feature heterogeneous microenvironments with limited nutrients like oxygen and glucose.
• The impact of oncogenic mutations on cellular stress responses and survival in these environments is not fully understood.

Purpose of the Study:

• To investigate how constitutive mammalian target of rapamycin complex 1 (mTORC1) activity affects cellular responses to hypoxia.
• To determine the role of lipids in cell survival under nutrient-limiting conditions in cancer cells with dysregulated growth pathways.

Main Methods:

• Utilized Tsc2(-/-) (tuberous sclerosis complex 2(-/-)) cells to model constitutive mTORC1 activity under hypoxic conditions.
• Assessed the unfolded protein response (UPR), endoplasmic reticulum (ER) expansion, and cell death pathways.
• Investigated the effect of exogenous unsaturated lipid supplementation on cell survival.

Main Results:

• Hypoxic Tsc2(-/-) cells with limited serum lipids showed a magnified UPR and inositol-requiring protein-1 (IRE1)-dependent cell death due to failed ER expansion.
• Cell death was reversed by adding unsaturated lipids, indicating a dependency.
• UPR activation and apoptosis were observed in Tsc2-deficient kidney tumors and multiple human cancer cell lines.

Conclusions:

• Constitutive mTORC1 activity induces a dependency on exogenous desaturated lipids in hypoxic cancer cells.
• Cancer cells in ischemic tumor microenvironments struggle to balance lipid and protein synthesis due to desaturated lipid deficiency, leading to cell death.
• Targeting lipid metabolism could be a therapeutic strategy for cancers with dysregulated mTORC1 signaling.