Exploring the paradigm shift in cancer treatment through metabolic reprogramming, featuring key research from the 2nd International Conference for Cancer Metabolism and Therapy
In October 2017, nearly 200 leading scientists gathered in Wenzhou, China, for the 2nd International Conference for Cancer Metabolism and Therapy. Their shared mission: to crack the code of how cancer cells rewire their metabolic machinery to fuel uncontrolled growth. While genetic mutations have long dominated cancer research, this conference spotlighted a crucial insight—cancer is as much a metabolic disease as it is a genetic one 1 .
"Cancer metabolism is intimately linked to drug resistance, which is currently one of the most important challenges in cancer therapy" 1 .
The conference proceedings revealed a paradigm shift in our understanding of cancer's inner workings. This recognition—that metabolic reprogramming contributes significantly to treatment failure—has opened exciting new avenues for therapeutic intervention. Researchers are now learning to exploit these very metabolic adaptations as Achilles' heels that might be targeted with unprecedented precision.
One of the oldest observations in cancer biology reveals that cancer cells preferentially use aerobic glycolysis—they convert glucose to lactate even when oxygen is plentiful 2 .
This seemingly inefficient strategy provides not just energy but also building blocks for creating new cells: carbon skeletons for amino acids, glycerol for lipids, and intermediates for nucleotide synthesis 2 .
Cancer doesn't grow in isolation. Tumor cells interact with and modify their surrounding tumor microenvironment, which includes blood vessels, immune cells, and fibroblasts 1 .
"Heterogeneity of tumor microenvironment may be resulted from dysregulated metabolic phenotypes" — Professor G.G. Xiao, Dalian University of Technology 1 .
His team hypothesized that cell phenotype alterations begin with early metabolic signals that eventually alter genomic and proteomic profiles—suggesting that metabolism drives cancer diversity rather than merely resulting from it.
The concept of targeting cancer metabolism isn't entirely new. Some of the earliest effective chemotherapies were antimetabolites—drugs that mimic natural metabolites and disrupt essential biochemical processes 2 .
| Drug | Target | Primary Cancer Applications |
|---|---|---|
| Methotrexate | Dihydrofolate reductase | Leukemia, lymphoma |
| 5-Fluorouracil | Thymidylate synthase | Gastrointestinal cancers |
| 6-Mercaptopurine | PRPP amidotransferase | Acute lymphoblastic leukemia |
| L-Asparaginase | Asparagine depletion | Acute lymphoblastic leukemia |
Conference presentations highlighted several promising new targets for manipulating cancer metabolism:
Found to promote pancreatic cancer progression by enhancing glycolysis 8 .
Often silenced in cancers; its restoration reduces tumor proliferation and metastasis 1 .
Regulates lipid metabolism and acts as a checkpoint against cancer development 1 .
Proteins like p62/SQSTM1, when modified, can enhance cellular cleanup processes under stress 1 .
One particularly compelling study presented at the conference came from researchers at Shanghai Jiao Tong University, who investigated a potential metabolic vulnerability in pancreatic ductal adenocarcinoma (PDAC)—one of the most aggressive and treatment-resistant cancers 8 .
The team focused on the P2Y2 purinergic receptor, which had been observed at high levels in PDAC patients with poor prognosis. They hypothesized that this receptor, when activated by extracellular ATP abundant in the tumor microenvironment, might reprogram cancer cell metabolism to support tumor growth.
First, they examined P2RY2 expression in 264 human PDAC samples and correlated it with patient survival.
They blocked P2RY2 using both a selective antagonist (AR-C 118925XX) and shRNA-mediated gene silencing in human PDAC cell lines.
They assessed changes in glycolysis and tumor cell viability after P2RY2 inhibition.
Using RNA sequencing, they mapped the downstream signaling pathways affected by P2RY2 blockade.
They tested their findings in multiple PDAC mouse models, including an inflammation-driven model that mimics the human disease progression.
The findings were striking. Activated P2RY2 receptor was found to engage in crosstalk with PDGFR, mediated by the Yes1 protein, which triggered the PI3K/AKT-mTOR signaling cascade 8 . This resulted in elevated expression of two key metabolic regulators: c-Myc and HIF1α, which subsequently enhanced cancer cell glycolysis.
| Experimental Model | P2RY2 Inhibition Method | Observed Outcome |
|---|---|---|
| Human PDAC cell lines | Pharmacological (AR-C 118925XX) | Reduced cancer cell viability and clonogenicity |
| Human PDAC cell lines | Genetic (shRNA) | Impaired glycolytic capacity |
| Xenograft mouse models | Pharmacological inhibition | Delayed tumor progression |
| Inflammation-driven PDAC model | Genetic and pharmacological approaches | Impaired tumor growth |
| Gemcitabine combination | AR-C 118925XX + chemotherapy | Prolonged survival in PDAC mice |
When researchers combined the P2RY2 antagonist with gemcitabine (a standard chemotherapy for pancreatic cancer), they observed significantly prolonged survival in mouse models 8 . This suggests that targeting this metabolic pathway could enhance the effectiveness of existing treatments.
The study provides a compelling example of how understanding and targeting cancer metabolism might lead to new therapeutic options for even the most aggressive cancers. As the authors concluded, "P2RY2 may be a potential metabolic therapeutic target for PDAC" 8 .
Advances in cancer metabolism research depend on sophisticated tools and technologies. Conference presentations highlighted several essential reagents and methods enabling progress in this field:
| Tool/Technology | Function/Application | Examples from Research |
|---|---|---|
| Stable isotopomer tracing | Tracking nutrient fate through metabolic pathways | Measuring quantitative metabolic fluxes in cancer cells 1 |
| RNA sequencing | Revealing global changes in gene expression | Identifying downstream pathways of metabolic regulators 8 |
| Metabolic inhibitors | Specifically blocking metabolic enzymes or transporters | Using 2-DG to inhibit hexokinase and glucose metabolism 2 |
| Genetically engineered mouse models | Studying cancer metabolism in living organisms | Mdm2C305F mice to study RP-Mdm2-p53 pathway in lipid metabolism 1 |
| Mass spectrometry | Identifying protein modifications and interactions | Mapping ubiquitylation sites on autophagy receptor p62 1 |
These tools have enabled researchers to move beyond simple observations of metabolic changes to understanding the precise mechanisms and consequences of metabolic reprogramming in cancer.
The research presented at the 2nd International Conference for Cancer Metabolism and Therapy reveals a field at a pivotal moment. Once considered a secondary consequence of cancer, metabolic reprogramming is now recognized as a fundamental hallmark of the disease—and a promising therapeutic target.
"Progress in targeting cancer metabolism therapeutically in the past decade has been limited," with only a few metabolism-based drugs successfully developed 6 .
However, the growing understanding of how metabolic pathways interact with the tumor microenvironment and immune system is opening new possibilities.
The future of cancer metabolism research lies in personalized approaches that account for the metabolic heterogeneity of different cancers and individual patients. It will require considering not just cancer cell metabolism but also how therapeutic interventions affect the metabolism of immune cells and other components of the tumor microenvironment 6 .
As we continue to unravel the complex metabolic wiring of cancer cells, we move closer to therapies that can selectively starve tumors while sparing healthy tissues—potentially with fewer side effects than conventional treatments. The work shared in Wenzhou represents important steps toward that goal, proving that sometimes, the most promising approaches come from looking at old problems through a new metabolic lens.