How Lung Cancer's Appetite Changes as It Spreads
The key to stopping cancer's deadly spread may lie in understanding its evolving diet.
Imagine two tumors, born from the same genetic blueprint, yet behaving as metabolic opposites. This is the paradoxical reality facing lung cancer researchers, who have discovered that the same cancer can develop strikingly different appetites as it travels throughout the body.
The revelation comes thanks to advanced imaging techniques that can precisely measure tumor metabolism, revealing that cancer's sugar consumption varies considerably between its original site and new metastatic locations. This discovery is reshaping our understanding of cancer progression and opening new avenues for treatment.
To understand why this discovery matters, we must first explore one of cancer's most fundamental characteristics: its unique metabolism. Nearly a century ago, German scientist Otto Warburg observed that cancer cells consume glucose at an astonishing rate, even when oxygen is plentiful 1 . This phenomenon, now known as the Warburg effect or aerobic glycolysis, distinguishes cancer cells from their normal counterparts.
Normal cells efficiently convert glucose into energy through oxidative phosphorylation in mitochondria, producing up to 36 ATP molecules per glucose molecule.
Cancer cells prefer to rapidly ferment glucose into lactate, even though this process produces far less energy (only 2 ATP molecules per glucose molecule) 1 .
The answer lies in cancer's need for more than just energy. This glycolytic pathway provides:
In lung cancer, this metabolic reprogramming is driven by activated oncogenes like MYC, which increases the expression of glucose transporters and glycolytic enzymes, essentially building a more efficient sugar-importing and processing machinery within the cancer cell 1 .
Detecting and measuring cancer metabolism in living patients became possible with the development of fluorodeoxyglucose posit emission tomography (FDG-PET) scanning. Before a PET scan, patients receive an injection of FDG, a radioactive glucose analog that accumulates in cells with high metabolic activity 8 .
The brightness of different areas on PET scans is quantified using standardized uptake value (SUV) numbers. Think of SUV as a tape measure for radioactive activity in the body 8 . Generally, higher SUV numbers indicate more metabolic activity, which often corresponds to malignant growth 8 .
Simulated SUV values showing metabolic activity differences
When a tumor is smaller than two to three times this resolution, its radioactivity appears diluted or "spills over" into surrounding tissues 7 . The consequence? Underestimation of true metabolic activity in small tumors, potentially leading to mischaracterization of tissue structures and even misdiagnosis 7 .
Partial volume correction (PVC) techniques have been developed to address this limitation. These methods use mathematical approaches to compensate for the blurring effect, recovering the true activity concentrations that would be measured with a perfect scanner 2 7 . As one research team noted, "appropriate PVC may enhance the brain network structure analysis for AD progression and improve classification performance" 2 —a principle that equally applies to cancer imaging.
The application of PVC techniques has revealed a fascinating pattern in lung cancer: significant differences in glucose metabolism between primary and metastatic tumors. This variation represents "a new observation" that challenges previous assumptions about cancer metabolism.
Genomic comparisons between primary and metastatic cancers offer clues. A pan-cancer whole-genome comparison study revealed that metastatic cancers generally display:
Hypothetical metabolic activity across common metastatic sites
These genetic differences likely contribute to the metabolic variations observed between primary and metastatic sites. The metastatic environment itself—whether bone, liver, or brain—may also impose unique selective pressures that shape metabolic preferences.
Recent research has uncovered another dimension of cancer metabolism that extends beyond glucose. A 2025 study published in Nature Metabolism revealed that glycogen accumulation drives tumor initiation and progression in lung adenocarcinoma 6 .
Glycogen, typically considered an energy storage molecule, appears to play a previously underappreciated role in cancer.
Through high-throughput spatial analysis of human lung adenocarcinoma samples, researchers discovered that:
Glycogen accumulation correlates with increased tumor grade and poor survival
Dietary or genetic interventions that increase glycogen levels accelerate tumor progression
The study developed a multiplexed spatial technique to simultaneously assess glycogen and cellular metabolites, uncovering "a direct relationship between glycogen levels and elevated central carbon metabolites essential for tumour growth" 6 . This finding positions glycogen as a critical and previously underexplored oncogenic metabolite in lung cancer.
Understanding cancer metabolism requires specialized tools and approaches. The table below details essential reagents and methods used in this field of research:
| Research Tool | Function/Application | Example/Notes |
|---|---|---|
| FDG-PET Imaging | Measures glucose metabolism in vivo | Clinical standard for cancer detection and monitoring 8 |
| Partial Volume Correction | Corrects spillover effects in PET imaging | Improves quantitative accuracy; multiple methods exist 2 7 |
| Spatial Metabolomics | Simultaneously maps multiple metabolites in tissue | Revealed glycogen-cancer connection 6 |
| 2-Deoxy-D-Glucose (2-DG) | Inhibits hexokinase in glycolysis | Experimental therapeutic; reverses drug resistance in NSCLC 1 |
| WZB117 | GLUT1 transporter inhibitor | Reduces glucose uptake in A549 lung cancer cells 1 |
| Glycogen Synthase Ablation | Genetic suppression of glycogen production | Suppressed tumor growth in experimental models 6 |
These metabolic insights are already driving innovations in lung cancer care. The ability to accurately measure tumor metabolism through PVC-corrected SUV values has significant implications:
SUV numbers often change before noticeable tumor size alterations, providing earlier indicators of treatment effectiveness 8
Metabolic vulnerabilities differ between primary and metastatic sites, suggesting potentially tailored approaches
Glycogen metabolism represents a promising new therapeutic target 6
Recent clinical advances highlight the progress in lung cancer treatment. At the 2025 ASCO meeting, researchers presented promising results for several targeted therapies:
A bispecific T-cell engager that reduced death risk by 40% compared to chemotherapy in recurrent small cell lung cancer 5
An oral targeted therapy effective against lung cancers with EGFR exon 20 insertion, even after other treatments fail 5
Given before surgery to EGFR+ NSCLC patients, resulting in significantly better responses than chemotherapy alone 5
The discovery that tumor metabolism varies between primary and metastatic sites represents more than an academic curiosity—it reveals cancer's metabolic plasticity and adaptability. This understanding is driving a paradigm shift in how we approach cancer treatment, moving toward increasingly personalized strategies that account for both genetic and metabolic differences within the same patient's cancer.
As research continues, scientists hope to develop therapies that specifically target the metabolic dependencies of both primary and metastatic tumors, potentially cutting off the fuel supply that drives cancer progression and spread. The future of oncology may well depend on understanding and disrupting cancer's evolving diet—a feat made possible by technical advances in measuring the subtle metabolic differences between a cancer's original and new homes.
The complex metabolic landscape of cancer continues to reveal new targets and therapeutic opportunities, offering hope for more effective, personalized treatments for patients with advanced disease.