One of the most stubborn killers in oncology is quietly being re-understood at the level of its molecular plumbing. Head and neck squamous cell carcinoma, or HNSCC, is the sixth most common cancer worldwide, with roughly 900,000 new cases each year and mortality rates approaching fifty percent. Surgery, radiation, chemotherapy, and immunotherapy have all advanced, yet patients with recurrent or metastatic disease still face grim odds, largely because tumors recur, spread, and shrug off treatment. A new open-access study published in Medical Oncology now adds a striking piece to the puzzle: researchers report that a well-known growth factor pathway does not merely tell these cancer cells to grow and move—it fundamentally rewires how they feed themselves, switching on a glutamine-burning metabolic program that could become a therapeutic bullseye.
The pathway in question is the hepatocyte growth factor (HGF)/c-MET axis, a receptor tyrosine kinase system that normally orchestrates embryonic development, tissue regeneration, and wound healing. In cancer, it is hijacked. Overexpression of c-MET has been documented in more than eighty percent of HNSCC cases and correlates with poor prognosis, and the pathway is implicated in resistance to EGFR-targeted drugs such as cetuximab. Earlier work from the same group had already shown that HGF stimulation ramps up glycolysis—the glucose-fermenting Warburg metabolism familiar from textbook cancer biology—in head and neck cancer cells. What remained unknown was whether the same signal also governs glutamine metabolism, the second great nutrient stream on which proliferating tumors depend.
Glutamine is far more than a backup fuel. For rapidly dividing cells it supplies both carbon and nitrogen for building nucleotides, amino acids, and lipids. The gatekeeper of this economy is glutaminase 1, or GLS-1, the rate-limiting enzyme that converts glutamine into glutamate, thereby feeding the tricarboxylic acid cycle and powering mitochondrial energy production. Elevated GLS-1 has been tied to aggressive behavior and poor outcomes in multiple cancer types. The Würzburg-led team, including first author Marius Hörner and senior author Stefan Hartmann, reasoned that if c-MET could commandeer glucose handling, it might also pull the levers of glutaminolysis—and that the connection could be exploitable.
To find out, the researchers compared basal GLS-1 levels in primary human oral keratinocytes—the non-malignant controls—with three HNSCC cell lines of distinct MET status: MET-amplified Detroit 562, originally derived from a pleural metastasis of a pharyngeal carcinoma, and the MET wild-type lines FaDu and SCC-154. The result was unambiguous. Every cancer line expressed more GLS-1 than normal keratinocytes, and the MET-amplified Detroit 562 cells showed the strongest basal expression. When the cells were bathed in recombinant HGF for twenty-four hours, only Detroit 562 responded dramatically: GLS-1 mRNA surged approximately 3.4-fold above control, and GLS-1 protein climbed several-fold on Western blot. FaDu and SCC-154 cells, lacking MET amplification, barely blinked. The metabolic reprogramming, in other words, was selective for cells with an amplified receptor.
The selectivity proved mechanistically decisive. Pretreating Detroit 562 cells with Foretinib, a selective c-MET inhibitor, completely abolished the HGF-driven rise in GLS-1, restoring expression to baseline, while the inhibitor alone left basal levels untouched. Functional assays tracked the metabolic consequences in the culture medium itself. After HGF stimulation, extracellular glutamine concentrations dropped significantly—evidence of increased consumption—while extracellular glutamate rose sharply, consistent with accelerated glutaminolysis. Foretinib prevented both changes, pinning the flux shift squarely on c-MET activity. For a cell line already prone to metastatic behavior, the growth factor was effectively upgrading its metabolic engine.
Next came the question of which intracellular cascade transmits the signal. Based on the group’s prior glucose-metabolism work, in which neither PI3K/AKT nor JAK/STAT contributed to the metabolic switch, attention turned to MAPK/ERK. The bet paid off. HGF triggered robust phosphorylation of ERK1/2 at Tyr204 in Detroit 562 cells, and the selective ERK1/2 inhibitor FR180204 completely blocked the HGF-induced increase in GLS-1 at both mRNA and protein levels. The signaling logic was thus clean: HGF binds c-MET, c-MET activates ERK, and ERK drives GLS-1 transcription—an oncogenic kinase cascade wired directly into a metabolic enzyme.
The functional fallout was equally clear. In wound-healing assays, HGF-stimulated Detroit 562 monolayers closed scratches at 65.4 percent after twenty-four hours and 89.7 percent after forty-eight hours, compared with 40.3 and 70.5 percent in untreated controls—a marked boost in motility. ERK inhibition erased this pro-migratory effect, and HGF also increased phosphorylation of focal adhesion kinase, a surrogate marker of migratory activity, in a c-MET-dependent fashion. When the researchers silenced GLS-1 with siRNA, wound closure slowed significantly, demonstrating that the enzyme is not a passive bystander but a functional requirement for HGF-driven migration. Cell proliferation markers fell in parallel.
Mitochondrial physiology told the same story with quantitative precision. Using Seahorse extracellular flux analysis, which tracks the oxygen consumption rate (OCR) of living cells through sequential injection of oligomycin, the uncoupler BAM15, and rotenone/antimycin A, the team showed that HGF significantly raised both basal and maximal mitochondrial respiration in MET-amplified Detroit 562 cells. GLS-1 knockdown dropped basal and maximal OCR and abolished the HGF-induced respiratory boost. In MET wild-type FaDu cells, by contrast, HGF left respiration unchanged, and GLS-1 silencing reduced OCR independently of HGF—confirming that the metabolic response is a specific property of the MET-amplified state, not a general feature of head and neck cancer cells.
Critically, the laboratory findings survived contact with real patient data. Mining RNA-sequencing data from 522 primary tumors in the TCGA-HNSC cohort, the researchers found a significant positive Spearman correlation between MET and GLS1 expression (ρ = 0.432, p < 0.0001), a weaker but significant link between HGF and GLS1 (ρ = 0.165), and the strongest correlation of all between a composite MAPK/ERK transcriptional activity score—built from ten established ERK target genes including DUSP6, MYC, and CCND1—and GLS1 expression (ρ = 0.581, p < 0.0001). Stratifying patients by median MET expression, MET-high tumors showed significantly higher GLS1, along with elevated SLC1A5, the glutamine transporter, whereas the related gene GLS2 did not differ—underscoring the specificity of GLS1-dependent glutaminolysis downstream of c-MET.
The therapeutic implications are tantalizing, though the authors are careful to frame them appropriately. Single-agent c-MET inhibitors such as Foretinib and Tivantinib have shown limited efficacy in HNSCC, but the new data suggest that dual targeting of c-MET and GLS-1 could circumvent compensatory signaling, and next-generation glutaminase inhibitors such as CB-839 have already demonstrated activity in other malignancies. The bispecific EGFR/MET antibody Amivantamab, approved in non-small cell lung cancer and now showing promising early results in the OrigAMI-4 trial for HNSCC patients who progressed on checkpoint inhibitors and chemotherapy, adds further momentum. Because c-MET signaling has also been linked to PD-L1 induction and glutamine availability shapes antitumor immunity, combining MET blockade, GLS-1 inhibition, and immunotherapy is an openly debated possibility. Caveats remain: the study relied on 2D culture models centered on a single MET-amplified line, intracellular isotope-tracing flux measurements were not performed, and in vivo efficacy was not tested. Validation in 3D spheroids, patient-derived organoids, and animal models will be essential. Still, the work expands c-MET’s portfolio beyond proliferation and migration into metabolic sovereignty—and in doing so, hands oncologists a second target in a cancer that desperately needs more than one.
Subject of Research: HGF/c-MET signaling drives glutamine metabolism via MAPK/ERK-dependent GLS-1 induction in MET-amplified head and neck squamous cell carcinoma
Article Title: HGF/c-MET signaling induces glutamine metabolism in MET-amplified head and neck squamous cell carcinoma via MAPK/ERK-dependent induction of GLS-1
Article References: HGF/c-MET signaling induces glutamine metabolism in MET-amplified head and neck squamous cell carcinoma via MAPK/ERK-dependent induction of GLS-1. (n.d.). https://doi.org/10.1007/s12032-026-03409-0
Image Credits: AI Generated
DOI: 10.1007/s12032-026-03409-0
Keywords: HNSCC, c-MET, HGF, GLS-1, glutamine metabolism, MAPK/ERK, Foretinib, glutaminolysis, TCGA, cancer metabolism, mitochondrial respiration, Head and neck cancer
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Nathaniel Bowman. (September 22, 2026). Cancer Cells Rewire Their Fuel Supply When This Growth Signal Switches On. Scienmag. https://scienmag.com/cancer-cells-rewire-their-fuel-supply-when-this-growth-signal-switches-on/
Nathaniel Bowman. “Cancer Cells Rewire Their Fuel Supply When This Growth Signal Switches On.” Scienmag, 22 September 2026, https://scienmag.com/cancer-cells-rewire-their-fuel-supply-when-this-growth-signal-switches-on/. Accessed 22 September 2026.
Nathaniel Bowman. “Cancer Cells Rewire Their Fuel Supply When This Growth Signal Switches On.” Scienmag. September 22, 2026. https://scienmag.com/cancer-cells-rewire-their-fuel-supply-when-this-growth-signal-switches-on/
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Tags: c-METcancer cell fuel supply rewiringcancer cell metabolism reprogrammingcancer growth signaling pathwayscancer metabolismForetinibGLS-1Glutamine Metabolismglutamine metabolism in tumorsglutaminolysishead and neck cancerhead and neck squamous cell carcinoma treatmenthepatocyte growth factor c-MET pathway in cancerHGFHNSCCMAPK/ERKmetabolic targets for cancer therapymetabolic vulnerabilities in cancer cellsmitochondrial respirationmolecular mechanisms of cancer progressiontargeted cancer therapy strategiesTCGAtherapy resistance mechanisms in oncologytumor recurrence and metastasis
