Cancer’s hidden engine: How metabolism could unlock a deadly childhood tumour

For more than a century, scientists have sought to understand cancer through the lens of uncontrolled cell division (the genetic mutations that drive relentless growth). Yet an older, often overlooked idea has persisted alongside this framework: that cancer is, at least in part, a disease of metabolism.

Now, new research into a rare and highly lethal liver cancer may be bringing that idea back into sharper focus. In work published in Cancers, a team led by Robert Nagourney at the Nagourney Cancer Institute has identified a striking vulnerability in fibrolamellar carcinoma—a rare form of liver cancer that predominantly affects adolescents and young adults. Instead of responding to conventional chemotherapy, these tumours appear unusually sensitive to drugs that disrupt cellular metabolism.

The findings suggest that, for this cancer at least, the key to treatment may lie not in DNA damage or cell cycle control, but in the biochemical pathways that fuel tumour cells.

A rare and stubborn disease

Fibrolamellar carcinoma is one of the most challenging cancers faced by clinicians. Affecting primarily individuals between the ages of 15 and 25, it is rare—fewer than a thousand cases are diagnosed annually worldwide—and notoriously resistant to standard chemotherapy.

Surgical removal remains the primary treatment, but recurrence is common. For patients with advanced disease, options are limited, and outcomes are often poor.

Part of the difficulty lies in the tumour’s biology. Fibrolamellar cancers are associated with a distinctive genetic rearrangement, known as DNAJB1-PRKACA, which alters cellular signalling pathways. However, this mutation has not translated easily into effective targeted therapies. Nagourney’s work suggests that this may be because researchers have been looking in the wrong place.

Rather than focusing solely on genetic drivers, the research team explored how these tumours behave functionally (how they respond to therapeutic agents and how they process energy).

Using a technique known as ex vivo analysis of programmed cell death (EVA/PCD), tumour samples taken from patients were exposed to a wide range of drugs. The method, developed at the Nagourney Cancer Institute, allows researchers to observe how cancer cells react to treatment before those therapies are administered to the patient.

Standard chemotherapeutic agents produced little effect, confirming the clinical reality of treatment resistance. However, when the researchers tested drugs that interfere with cellular metabolism, a very different picture emerged: the tumours appeared markedly sensitive.

To explore this further, the team turned to mass spectrometry, a powerful analytical tool capable of measuring metabolic byproducts in blood and tissue with high precision.

The results, according to Nagourney, were unmistakable: the tumour’s metabolic profile differed sharply from that of normal tissue.

“These metabolic signatures stood out clearly,” he noted, suggesting that fibrolamellar carcinoma is defined as much by its metabolic state as by its genetic mutations.

The concept that cancer is linked to altered metabolism is not new. In the 1920s, the biochemist Otto Warburg proposed that cancer cells rely on a distinct mode of energy production—now known as the “Warburg effect”. This theory argued that tumour cells preferentially use glycolysis rather than oxidative phosphorylation, even in the presence of oxygen.

For decades, however, cancer research has been dominated by genetic approaches, with metabolism often treated as a downstream consequence rather than a primary driver.

Recent advances in metabolomics (the study of small molecules involved in cellular processes) are changing that perspective. Techniques such as targeted mass spectrometry now allow researchers to quantify metabolic pathways in detail, opening new avenues for understanding tumour biology.

The fibrolamellar findings add to this growing body of evidence, suggesting that, in some cancers, metabolic disruption may be not only a feature but a fundamental cause. If fibrolamellar tumours depend on altered metabolic pathways, then drugs that disrupt those pathways could offer an effective treatment strategy. Unlike conventional chemotherapy, which broadly targets rapidly dividing cells, metabolic therapies can be more selective—interfering with processes that cancer cells rely on disproportionately.

Several such drugs already exist, developed originally for other indications. Repurposing these agents for rare cancers could accelerate the translation from research to clinical use.

Furthermore, the ability to test drug responses directly on patient-derived tumour samples offers a more personalised approach. Instead of relying on population-level data, clinicians could tailor treatment based on the unique metabolic profile of each tumour.

Canadian context: Growing interest in metabolomics

The implications of this work resonate beyond a single rare cancer. Canada, for example, has become a hub for metabolomics research, supported by initiatives such as Genome Canada and the Metabolomics Innovation Centre at the University of Alberta. These programmes are applying metabolic profiling to areas ranging from cancer diagnostics to precision medicine.

Canadian researchers have already demonstrated that metabolic signatures can help distinguish tumour types, predict treatment response and identify new therapeutic targets. The fibrolamellar study strengthens the case for integrating metabolomics more deeply into clinical oncology. It also highlights the potential for combining metabolic analysis with functional testing, linking what tumours are doing chemically with how they respond to drugs.

Challenges and caution

Despite its promise, the approach is not without challenges. Metabolism is highly complex, involving interconnected pathways that vary between tissues and individuals. Targeting one pathway may lead to compensatory changes elsewhere, reducing therapeutic effectiveness.

There are also practical considerations. Techniques such as mass spectrometry require specialised equipment and expertise, although advances in instrumentation are making these tools more accessible. For rare cancers like fibrolamellar carcinoma, patient numbers remain small, making large-scale clinical trials difficult. Collaboration between institutions—such as that seen in this study with the FibroFighters Foundation (https://fibrofighters.org)—will be essential.