In the sprawling metropolis of the human body, order is maintained by a careful system of governance. Every cell knows its duty, follows its genetic code, and contributes to the greater whole. But sometimes, amid the quiet rhythm of breast tissue, a rebellion stirs. This is breast cancer, a faction that looks like it belongs, yet works from within to undermine balance. Luminal cancers arise from cells that still display oestrogen and progesterone receptors, masquerading as diplomatic badges. These allow the cancer to blend in, hijack hormonal signals, and quietly build strength.
Modern medicine has fought back with hormone therapies, drugs that block receptors, and cut off cancer’s fuel like signal jammers in a digital war. Yet luminal cancers are resourceful. Some mutate and find alternate pathways; others lie low, waiting for the blockade to weaken. The immune system, normally a vigilant guard, struggles to recognise such familiar-looking foes without risking harm to healthy tissue. Luminal subtypes make up the majority of breast cancer cases worldwide, accounting for more than 50% of cases in India. They may not kill quickly, but their persistence, resistance, and ability to recur make them a formidable challenge- akin to the Hydra’s head that keeps growing back.
At the heart of this resistance lies metabolism, the cancer’s ability to rewire its energy and building blocks. In cancer cells, one of the important survival tricks comes from a specialized type of fat called sphingolipids. At first glance, they look like ordinary building blocks of cell membranes. But in reality, they act like secret couriers, carrying signals that tell cells when to grow, survive, or even resist treatment. When processed into gangliosides (a complex type of glycosphingolipid), they become even more powerful. Gangliosides can tweak how receptors on the cell surface behave, essentially boosting “growth signals” and making cancer cells harder to stop proliferating.
A recent study in PLOS Biology, led by Ujjaini Dasgupta at Ashoka University and Avinash Bajaj at Regional Center for Biotechnology, uncovered a key metabolic and gene regulatory circuit.
A protein called RICTOR, part of the mTORC2 complex (a central growth regulator), normally helps cells survive by activating AKT, a growth-promoting protein. But in luminal cancers, RICTOR goes further: it over activates a transcription factor called ZFX, and through AKT, it changes the cell’s epigenetic settings so that a key enzyme, UDP-glucose ceramide glucosyltransferase or UGCG, is switched on for a longer duration.
UGCG acts like a gateway: it converts simpler lipids (ceramides) into complex ones with a glucose residue (glucosylceramides), which then give rise to gangliosides. Among these, GD3 gangliosides are especially important because they supercharge EGFR, a receptor that drives cancer growth. This creates a vicious cycle; more gangliosides mean stronger signals, which keep the cancer growing and help it resist treatments.
What this study uncovered is not just a hijacked lipid supply line but a carefully wired metabolic and gene regulatory circuit. This circuit connects ganglioside metabolism with cancer progression through the EGFR – mTORC2/RICTOR complex, with multiple nodes: metabolite production, signalling pathways, and transcriptional changes, working together to keep the tumour growing.
One reason chemo-resistance has been so difficult to overcome is our incomplete understanding of how these networks operate and interconnect. Previous studies suggested that shutting down mTORC2 (a central metabolic regulator) or EGFR inhibition could cut off this advantage, but hitting these central hubs (mTORC2 or EGFRs) is like cutting power to an entire city- that may be effective but harmful to healthy systems.
By mapping the circuit, we identified UGCG as a precise choke point. Without it, cancer cells cannot make their protective gangliosides, and the cycle breaks. Recognising these as circuits opens the door to combinatorial strategies, where multiple nodes can be blocked at once, leaving cancer with no escape route”, says Ujjaini.
And here, a fascinating opportunity emerged: a drug called eliglustat, originally developed for Gaucher’s disease (a rare genetic disorder that causes glucosylceramides to build up in organs due to a deficiency in the glucocerebrosidase enzyme), is a known UGCG inhibitor. Though Eliglustat had been tested in breast cancer before, with promising results, more clarity on why it worked would be helpful. This study provided the missing link: eliglustat works because it disarms cancer’s metabolic escape route. In other words, it tricks the trickster by targeting the very mechanism of its proliferation. The implications extend far beyond one drug. “By uncovering how UGCG drives cancer progression, researchers now have a blueprint to design or repurpose other drugs that hit different components of the sphingolipid pathway. Instead of bluntly attacking metabolism, medicine can deliver precision strikes, blocking the cancer’s backup systems without crippling the rest of the body”, says Avinash.
What I enjoyed most about this project was the collaborative spirit of the team, each discussion brought fresh perspectives, and every experiment felt like a shared step forward”, adds Mohammad Nafees Ansari (the first author of this study).
Nafees further adds, “though we had started with a hypothesis to mimic the inhibition of mTORC2 in cancer cells by modulating the sphingolipid candidates, we ended up with an entire metabolic-signaling-gene regulatory circuit with multiple nodes that can be tapped to trick the cancer cells”.
Even more exciting, this approach could be pan-cancer. The sphingolipid – ganglioside axis is a major metabolic regulator across many cancers. Identifying more such circuits will allow researchers to combine strategies, hitting several survival nodes at once. This shift, from treating cancers as isolated problems to mapping their hidden metabolic networks, may be key to overcoming resistance, hopes Ujjaini and Avinash.
The war against cancer is rarely won in a single strike. It is a long campaign of adaptation, counter-adaptation, and persistence. Yet every new insight, like repurposing eliglustat and the discovery of such metabolic networks, reshapes the terrain. Cancer may be the ultimate trickster, but science is learning to play the same game. The rebellion is clever, but it’s not invincible.
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