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Chronic acidosis drives reversible metabolic plasticity and survival adaptation in multiple myeloma

ABSTRACT: Multiple myeloma (MM) is a plasma cell malignancy that evolves within the complex bone marrow microenvironment, where sustained extracellular acidosis remains an underexplored but biologically significant stressor. To investigate the long-term impact of acidotic stress, we developed MM cell models chronically cultured under mildly acidic conditions, mimicking the gradual acidification seen during disease progression. This approach revealed a biphasic cellular response: initial exposure impaired proliferation, triggered apoptosis, and disrupted metabolic activity, whereas prolonged acidification induced a dynamic, reversible state marked by metabolic recovery, mitochondrial remodeling, and restored growth. Transcriptomic profiling uncovered distinct gene expression programs associated with this chronic adaptation, including 11 genes strongly correlated with disease stage and overall survival in MM patients. These findings suggest that extracellular acidosis is not simply a metabolic byproduct but a persistent selective pressure that shapes MM progression through metabolic plasticity and clonal evolution.

ORGANISM(S): Homo sapiens

PROVIDER: GSE314522 | GEO | 2025/12/24

REPOSITORIES: GEO

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Project description:Lactic acidosis and hypoxia are two prominent tumor microenvironmental stresses that are both known to exert important influences on gene expression and phenotypes of cancer cells. But very little is known about the cross-talk and interaction between these two stresses. We performed gene expression analysis of MCF7 cells exposed to lactic acidosis, hypoxia and combined lactic acidosis and hypoxia. We found the hypoxia response elicited under hypoxia was mostly abolished upon simultaneous exposure to lactic acidosis. The repression effects are due to loss of HIF-1Î± protein synthesis under lactic acidosis. In addition, we showed lactic acidosis strongly synergizes with hypoxia to activate the unfold protein response (UPR) and inflammation response which are highly similar to amino acid deprivation responses (AAR). The statistical factor analysis of hypoxia and lactic acidosis responses indicated that ATF4 locus, an important activator in the UPR/AAR pathway, is amplified in subsets of breast tumors and cancer cell lines. Varying ATF4 levels dramatically affect the ability to survive the post-stress recovery from hypoxia and lactic acidosis and may suggest its selection of ATF4 amplification in human cancers. These data suggest that lactic acidosis interacts with hypoxia by both inhibiting the canonical hypoxia response and while activating the UPR and inflammation response. Gain of ATF4 locus may offer survival advantages to allow successful adaptation to frequent fluctuations of oxygen and acidity in tumor microenvironment. Collectively, our studies have provided linkage between the short-term transcriptional responses to the long term selection of the DNA copy number alterations (CNAs) under tumor microenvironmental stresses. RNAs from MCF7 cells exposed to control condition (ambient air ~21% O2, no lactate and neutral pH), lactic acidosis (ambient air, 10 mM Lactate and pH 6.7), hypoxia (1% pO2, no lactate and neutral pH) and the combined lactic acidosis and hypoxia (1% pO2, 10 mM Lactate and pH 6.7) condition for 24 hours were extracted by miRVana kits (Ambion) and hybridized to Affymetrix Human genome 133A 2.0 arrays with standard protocol.

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Chronic acidosis drives reversible metabolic plasticity and survival adaptation in multiple myeloma

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