ATM inhibition drives metabolic adaptation via induction of macropinocytosis

Area of Science:

• Cancer Biology
• Cellular Metabolism
• Tumor Suppression

Background:

• Macropinocytosis is a cellular process potentially aiding cancer cell survival in nutrient-poor environments.
• Ataxia-Telangiectasia mutated (ATM) is a tumor suppressor involved in metabolic reprogramming.
• The interplay between ATM, macropinocytosis, and cancer metabolism remains incompletely understood.

Purpose of the Study:

• To investigate the role of ATM suppression in regulating macropinocytosis and cancer cell survival.
• To explore the therapeutic potential of targeting ATM and macropinocytosis in cancer.
• To elucidate the metabolic alterations associated with ATM inhibition and their impact on nutrient uptake.

Main Methods:

• In vitro and in vivo experiments involving cancer cell lines and tumor models.
• Genetic suppression of ATM and pharmacological inhibition of macropinocytosis.
• Amino acid supplementation assays, BCAA uptake analysis, and metabolomics.

Main Results:

• Suppression of ATM significantly increased macropinocytosis, enhancing cancer cell survival under nutrient-poor conditions.
• Combined inhibition of ATM and macropinocytosis led to suppressed proliferation and induced cell death.
• Supplementation with BCAAs abrogated ATM-induced macropinocytosis and normalized BCAA levels in the tumor microenvironment.

Conclusions:

• Loss of ATM function promotes cancer cell survival by upregulating macropinocytosis for nutrient acquisition.
• Targeting ATM and macropinocytosis presents a potential therapeutic strategy.
• ATM-inhibited cancer cells exhibit a metabolic vulnerability related to BCAA uptake, offering a novel target for intervention.