On 18 March 2026, Westlake Laboratory and the School of Life Sciences at Westlake University, in partnership with Science/AAAS, hosted the first online symposium of the 2026 Westlake–Science Series, entitled “Rethinking Cancer Metabolism.”

The event featured three world-leading experts in the cancer metabolism field: Dr. Matthew Vander Heiden from Massachusetts Institute of Technology, Dr. Sarah-Maria Fendt from VIB-KU Leuven Center for Cancer Biology, and Dr. Ralph J. DeBerardinis from UT Southwestern Medical Center. The symposium was co-chaired by Dr. Xin Jin, Principal Investigator at the School of Life Sciences, Westlake University, and Dr. Stella Hurtley, Deputy Editor of Science.

Over 40,000 online participants joined the live broadcast and exchanged ideas with the speakers. The global audience included fellow researchers, academics, scientists and students from universities, hospitals, research institutions and pharmaceutical companies, who actively submitted their questions and ideas through the online portal.

RESEARCH HIGHLIGHTS

Talk 1: “Influence of metabolism on cancer” by Dr. Matthew Vander Heiden

The Vander Heiden Laboratory investigates how mammalian cell metabolism is adapted to support cancer initiation and progression. Current interests of the lab include: 1) identifying which metabolic processes create bottlenecks for cell proliferation; 2) determining how metabolism is different in different cancers, examining in detail the influence of tissue type, tumor genetics, and tumor microenvironment; and 3) understanding how diet and whole-body metabolism influence cell metabolism to modify cancer and other disease phenotypes.

Dr. Vander Heiden began with a wide-angle view of cancer metabolism, emphasizing that cancer-specific metabolic states arise from the interplay of three factors: (1) cellular lineage, (2) oncogenic signaling, and (3) the tissue microenvironment. To dissect how cancer cells adapt metabolically to distinct organ sites, his team quantified absolute levels of nutrient metabolites in interstitial fluids from various mouse tissues and correlated nutrient availability with the capacity of metastatic breast-cancer cells to grow in each tissue. Using CRISPR editing, they engineered breast cancer cells with broad metastatic potential to be auxotrophic for specific nutrients, including purines, pyrimidines, and several amino acids, and then assessed their ability to colonize different organs. The results revealed a surprising finding that no single nutrient dictated metastatic outgrowth. For instance, de novo purine synthesis proved essential for metastasis in multiple organs, regardless of local nucleotide abundance or tumor intrinsic biosynthetic activity. Unbiased metabolomic analysis further revealed that a panel of selective metabolites, many of which previously under-investigated, correlate with organ-specific metastatic patterns, suggesting that the combinations of micro-environmental nutrients cooperate to determine potential sites of metastatic cancer growth. Together, the data argue that a complex interplay between multiple nutrients within the microenvironment and intrinsic cellular properties shapes metastatic potential of breast cancer.

From these observations, Dr Vander Heiden proposed a “metabolic-budget” model: cancer cell metabolic reprogramming is governed by regulatory “budget switches” that determine whether a cell relies on environmental supplies or activates its own biosynthetic pathways for different metabolites. He illustrated this concept with their recent work on serine metabolism. When extracellular serine is scarce, cancer cell lines display widely varying growth defects that correlate with their ability to up-regulate endogenous serine biosynthesis. The decisive variable, Dr. Vander Heiden identified, is the cell’s capacity to raise its NAD⁺/NADH ratio by boosting mitochondrial respiration after serine withdrawal. Lines that can enhance mitochondrial respiration regenerate NAD⁺ more efficiently, sustain higher serine production, and continue proliferating, independent of serine synthesis enzyme expression. In this case, mitochondrial NAD⁺ regeneration acts as the critical “budget” that governs whether oxidative biosynthesis and thus proliferation can proceed under nutrient stress.

In summary, Dr Vander Heiden’s presentation underscored the layered regulatory logic that allows cancer cells to balance nutrient uptake with self-synthesis, revealing how microenvironmental cues and intrinsic circuitry together dictate metastatic fitness.

Talk 2: “Fueling metastasis: Metabolic crosstalk with the organ microenvironment” by Dr. Sarah-Maria Fendt

The Fendt Laboratory tackles cancer and in particular metastasis formation as a metabolic disease. The lab employs spatial metabolomics and other cutting-edge technologies to mechanistically dissect the metabolic vulnerabilities of (metastasizing) cancer cells in the context of the tumor microenvironment and the metastatic niche to define novel therapeutic approaches to prevent cancer progression.

Metastasis is notoriously inefficient; disseminated cancer cells must overcome multiple bottlenecks, chief among them a limited nutrient supply in distant organs. Yet once they do, the resulting lesions can be devastating. Dr Fendt set out to identify the specific metabolic factors that enable these rare metastatic cells to flourish. Focusing on breast cancer lung metastases, her team employed quantitative metabolomics to profile the nutrient landscape of interstitial fluid from patient samples and mouse models, generating detailed metabolic portraits of the metastatic niche. They discovered that lipid levels—especially palmitate—were markedly elevated around metastatic lesions in comparison to normal lungs. Spatial metabolomics revealed that palmitate was highly enriched in the micro-environment immediately surrounding metastases. Single-cell RNA-seq identified alveolar type II (AT2) epithelial cells adjacent to tumors as the dominant source, exhibiting elevated lipogenic gene expression and heightened proliferation. As the metastasis progresses, both AT2-cell accumulation and palmitate abundance become more intensified. Mechanistically, Dr. Fendt showed that IL-6 secreted by tumor cells activate SREBP signaling in AT2 cells, up-regulating FASN and GPAM, key enzymes mediating palmitate production. As a result, conditional deletion of Fasn in AT2 cells or systemic inhibition of FASN or GPAM, diminished palmitate levels and impaired lung metastasis growth.

How do these environmental-derived palmitates promote breast cancer metastatic growth? Functional assays went on to demonstrate that the promoting effect depends on cancer cells’ palmitoyltransferase DHHC20. DHHC20 transfers palmitate to its substrate transmembrane 4L six family member 1 (TM4SF1). Palmitoylation of TM4SF1 promotes its plasma membrane localization, and in turn fosters non-canonical STAT3 signaling activation. Silencing DHHC20 or TM4SF1, or expressing a palmitoylation-deficient TM4SF1 mutant, curtailed lung metastasis formation.

Together, Dr Fendt’s presentation revealed a “metabolic vicious cycle” between cancer cells and AT2 stroma that sustains metastatic growth. Her work uncovers that microenvironment-derived palmitate acts not merely as a nutrient but also as a signaling modifier, expanding our view of metabolite function in metastasis.

Talk 3: “Metabolic reprogramming and human disease phenotypes” Dr. Ralph J. DeBerardinis

The DeBerardinis Laboratory is interested in the role of altered metabolic states in human diseases, particularly pediatric inborn errors of metabolism and cancer. The lab seeks to characterize these metabolic disorders, understand how they compromise tissue function, develop methods to monitor metabolism in vivo, and design therapies to restore normal metabolism and improve health.

Dr. DeBerardinis showcased clinical applications of in vivo metabolite isotope tracing, illustrating how it can map the metabolic activity landscapes of the primary tumors, metastases and normal tissues. His analyses revealed wide heterogeneity between different cancers yet a consistent trend: tumors with elevated mitochondrial metabolism, as evidenced by higher TCA-cycle labeling, are more prone to metastasize and exhibit worse clinical outcomes. In mouse models, oxidative phosphorylation accelerates metastasis whereas its inhibition delays progression. The key underlying factor, Dr. DeBerardinis explained, appears to be the cellular redox state that is set in part by the mitochondrial activity.

Dr. DeBerardinis further noted that the most profound metabolic change they observed upon mitochondrial metabolism perturbation is purine synthesis. His team focused on this biological process and delineated its balance control. Cells maintain their purine nucleotide pool through the orchestrated action of two complementary routes, the de novo purine biosynthesis (DNPB) and the purine salvage pathway. Purine salvage represses DNPB to prevent excessive purine nucleotide synthesis through unclear mechanisms. He showed that 6-thioguanine (6-TG), an antimetabolite chemotherapeutic, activates purine salvage while suppressing DNPB, shifting cells from DNPB to the salvage pathway. Using functional genetic screens, they pinpointed Nudix hydrolase 5 (NUDT5) as a pivotal regulator of this process. During salvage activation, NUDT5 binds directly to the DNPB rate-limiting enzyme PPAT, suppressing its activity. This binding is independent of NUDT5’s hydrolase function. AlphaFold structural modeling coupled with biochemical assays confirmed that the NUDT5-PPAT interaction promotes PPAT oligomerization, inhibits its enzymatic function and induces disassembly of the purinosome—the multienzyme complex that executes DNPB. Disrupting NUDT5-PPAT interaction relieved DNPB suppression, causing excessive purine synthesis and thiopurine resistance. Consistent with these findings, GWAS analyses linked NUDT5 expression to thiopurine sensitivity in acute lymphoblastic leukemia patients.

Collectively, these findings reveal how NUDT5 balances DNPB and salvage pathways to maintain nucleotide homeostasis. Dr. DeBerardinis’ research opens new directions for exploring the spatial organization and flux control of metabolic pathways within the cell.

Panel Discussion

The symposium concluded with an open Q&A session, during which speakers and moderators exchanged insightful and innovative perspectives. The discussion covered diverse topics, including metabolic vulnerabilities as potential therapeutic targets, their similarities and differences from classical oncogenic drivers, and future research priorities and translational prospects.

Science/AAAS and Westlake University Symposium 2026 Series

#1 | March 18, 2026

Rethinking Cancer Metabolism

Webpage:

https://lifesciences.westlake.edu.cn/media/events/20260318/rethinking-cancer-metabolism-2026-symposium-01.html