Introduction
Cancer cells constantly face metabolic challenges: insufficient nutrients, low oxygen (hypoxia), and accumulation of acidic by-products. These conditions create a hostile tumor microenvironment that, paradoxically, cancer cells exploit to drive growth, metastasis, and treatment resistance. Recent research published in Science (Oct 9, 2025) reveals how tumor acidosis orchestrates adaptations of energy metabolism to promote stress resilience in cancer, particularly pancreatic cancer. This deepens our understanding of cancer metabolism and uncovers novel strategies to target the metabolic flexibility of tumors.
Understanding Tumor Acidosis
What Is Tumor Acidosis?
As tumors grow rapidly, they outpace their blood supply, leading to localized hypoxia and nutrient deprivation. Cancer cells compensate by shifting to anaerobic glycolysis, producing lactic acid that acidifies the microenvironment (pH 6.5–6.9 vs. normal pH 7.4). This acidic milieu—tumor acidosis—was long seen as merely a by-product of metabolism. However, it is now recognized as an active player shaping tumor progression.
Impact on Cancer Cells
Tumor acidosis influences multiple cellular processes:
- Cell proliferation and survival: Acidic pH activates stress response pathways that help cancer cells resist apoptosis.
- Invasion and metastasis: Acidosis degrades the extracellular matrix, facilitating cancer cell migration.
- Drug resistance: Lower pH impairs the uptake of chemotherapy agents and promotes resistance mechanisms.
The new study sheds light on a critical mechanism: acidosis-mediated rewiring of energy metabolism through modulation of the ERK signaling pathway and mitochondrial dynamics.
ERK Signaling: A Central Regulator
ERK Pathway Basics
The extracellular signal-regulated kinase (ERK) pathway belongs to the MAPK signaling cascade, governing key processes like cell growth, differentiation, and survival. Under normal conditions, ERK activation promotes mitochondrial fission via phosphorylation of mitochondrial fission factors, maintaining a dynamic balance between fusion and fission.
Acidosis Suppresses ERK Activity
Under acidic stress, ERK activity in the cytoplasm is significantly suppressed. The study used sequential CRISPR screens in cancer cell lines and orthotopic pancreatic tumor models to identify genes crucial for survival under metabolic stress. One of the top hits was the downregulation of ERK signaling in acidic conditions.
- Mechanism: Acidosis perturbs upstream activators of ERK (e.g., MEK), reducing phosphorylation of ERK1/2.
- Consequence: Lower ERK activity prevents excessive mitochondrial fragmentation, tipping the balance toward mitochondrial fusion.
Mitochondrial Fusion Boosts Respiration
Mitochondrial Dynamics Overview
Mitochondria constantly undergo fusion (joining) and fission (splitting) to maintain function, distribution, and quality control. Fused mitochondria form elongated networks optimized for oxidative phosphorylation (OXPHOS), while fragmented mitochondria support glycolytic adaptation and rapid proliferation.
Fusion Enhances Bioenergetic Capacity
With ERK suppressed by acidosis, mitochondrial fusion is favored. The study demonstrated:
- Increased mitochondrial length and network connectivity in cancer cells cultured at acidic pH.
- Elevated oxygen consumption rate (OCR) is indicative of higher mitochondrial respiration.
- Enhanced ATP production through OXPHOS, supporting survival during nutrient scarcity.
In pancreatic tumors grown in mice, regions of higher acidity correlated with markers of mitochondrial fusion and increased respiration, confirming in vivo relevance.
Adaptations to Multiple Metabolic Stresses
Nutrient Shortage
Cancer cells in nutrient-poor environments benefit from fused mitochondria’s efficient ATP generation. Acidosis-driven fusion allows cells to extract maximum energy from limited substrates, maintaining viability and proliferation.
Hypoxia
Although hypoxia reduces OXPHOS due to low oxygen, the fused mitochondrial network provides resilience by:
- Maximizing residual respiratory capacity when oxygen is transiently available.
- Supporting redox balance through enhanced electron transport chain efficiency.
By-Product Accumulation
Acidosis itself stems from metabolic by-products. The study found that cancer cells adapted to acidic stress were better equipped to detoxify reactive oxygen species (ROS), preventing oxidative damage.
Pancreatic Cancer: A Case Study
Why Pancreatic Tumors?
Pancreatic ductal adenocarcinoma (PDAC) is notorious for its dense stroma, poor vascularization, and highly acidic microenvironment. The study focused on PDAC models because:
- PDAC survival rates are low due to resistance to chemotherapy and radiation.
- The harsh microenvironment plays a pivotal role in treatment failure.
Therapeutic Implications
Targeting acidosis-induced metabolic adaptations offers promising avenues:
- ERK Reactivation: Pharmacologically restoring ERK activity in acidic regions could rebalance mitochondrial dynamics toward fragmentation, making cells more vulnerable to stress.
- Fusion Inhibitors: Drugs that block mitochondrial fusion proteins (e.g., MFN1/2 inhibitors) may sensitize cancer cells to nutrient deprivation.
- pH Modulation: Buffer therapies to neutralize tumor acidity, combined with metabolic inhibitors, could disrupt the protective effects of acidosis.
Optimizing Cancer Therapy: Next Steps
Combination Strategies
Combining agents targeting acidosis adaptations with standard-of-care therapies could overcome resistance:
- Chemotherapy + Fusion Inhibition: Enhanced drug uptake in fragmented mitochondria.
- Radiation + ERK Modulation: Increased ROS sensitivity when mitochondrial networks are disrupted.
- Immunotherapy + pH Buffers: Improved immune cell infiltration and function in less acidic microenvironments.
Biomarker Development
Identifying biomarkers of mitochondrial fusion and acidosis (e.g., plasma lactate levels, imaging of pH gradients) can guide patient selection for these targeted treatments.
Conclusion
Tumor acidosis is not just a metabolic by-product; it actively reprograms cancer energy metabolism through suppression of ERK signaling and promotion of mitochondrial fusion. This adaptation equips cancer cells—particularly in pancreatic tumors—to thrive under nutrient scarcity, hypoxia, and oxidative stress. By unraveling these mechanisms, researchers have uncovered novel targets and strategies to undermine the metabolic resilience of tumors, paving the way for more effective combination therapies against aggressive cancers.