Pancreatic cancer cells take turns burning energy, like a group of workers sharing a single power tool to avoid draining the battery. These cells switch metabolic states in rhythmic waves, coordinated by a molecular pacemaker involving IL6, STAT3, and SOCS3—a delayed negative feedback loop similar to the body’s circadian clock. This matters because pancreatic ductal adenocarcinoma (PDAC) grows aggressively, yet tumours rarely run out of fuel. Standard lab tests miss this time-sharing behaviour because they measure static snapshots of metabolites, not dynamic rates of energy use. The researchers suspect that metabolic oscillations allow the tumour to ration resources, preventing self-imposed starvation. If they can disrupt this rhythm, the tumour may deplete its own energy supply. The project will screen PDAC cell lines for energy efficiency, verify the oscillator mechanism using fluorescent reporters, and run CRISPR screens to find genes that enable this resource-smart growth. Mouse xenografts will test whether disabling the rhythm generator slows tumour expansion. This is fundamental science. It does not promise an immediate treatment, but understanding how cancer cells coordinate metabolism could eventually reveal new therapeutic vulnerabilities—much like circadian rhythm research unexpectedly illuminated treatments for sleep disorders and jet lag.
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In many tissues (epithelia, muscle, neurons), electrical or neurohormonal signals activate metabolism at times of heightened demand to ensure efficient use of resources. These cues are typically lost in cancers, but resource-efficiency remains important, particularly when oncogenic mutations instruct a programme of rapid growth that could lead to self-limiting depletion of tumour resources. Sustainable use of resources may be implemented through rationing, whereby cohorts of cancer cells take turns to engage in energy-intensive activities (e.g. biomass growth, division). We believe this explains the emergence of metabolic heterogeneity. However, time-dependent phenomena evade discovery pipelines based on steady-state measurements of gene expression, protein abundance, or metabolite levels. We developed a method for sorting cells by a surrogate of fermentative flux, as opposed to steady-state metabolite concentrations which do not predict rates. Applying this to rapidly-growing pancreatic ductal adenocarcinoma (PDAC) cells, we described a signalling cascade that alternates metabolic state between basal and activated1. Operating as a delayed negative feedback circuit (akin to pacemakers, e.g. circadian), the cascade is triggered by interleukin 6 (IL6) receptors activating STAT3, which stimulates fermentation and respiration alongside transcription of its negative regulator SOCS3. Such a system can produce metabolic rhythms independently of cell-cycling. Since it is not hardwired, a population of such metabolic oscillators maintains dynamic heterogeneity, without drifting. We propose that our mechanism rations resources for energy-efficient PDAC expansion, and that its inactivation would eventually deplete resources, i.e. have therapeutic value. This project will: Screen a panel of PDAC lines for energy-efficiency of growth using real-time measurements of fermentative/respiratory fluxes and biomass, and relate this to metabolic phenotype and its heterogeneity. We will use single-cell assays and sorting methods developed by our group. Ranking by energy-efficiency will enable correlative discovery. Verify the delayed negative feedback mechanism. Metabolic sub-populations will be tested for IL6-STAT3-SOCS3 markers and oscillator kinetics will be tracked using a fluorescent reporter of STAT3 transcriptional activity after sequential sorting. Oscillator properties will be manipulated, e.g. changes to PEST motif that affect SOCS3 degradation. Identify genetic regulators that enable resource-smart growth using a CRISPR/Cas9 screen under limited resources (closed system), relative to unlimited resources (superfused system). The effect of inactivating candidate-genes on 'resource-smart' growth will be validated using competition assays with wild-type cells. Test vulnerabilities in the rhythm-generator as a therapeutic strategy by growing mouse xenografts comprising efficiency-compromised and wild-type cells.
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