A pioneering journey into cancer metabolism and the Hedgehog signaling pathway
Imagine if we could starve cancer cells by disrupting their favorite food source, all while leaving healthy cells untouched. This isn't science fiction—it was the pioneering work of Alberto Gulino, an Italian scientist whose research revealed how certain cancers become addicted to sugar and how we might exploit this vulnerability.
Born in 1952, Gulino would become one of Italy's most influential molecular biologists, whose discoveries opened new pathways in understanding how cancer cells hijack our body's normal developmental processes 1 . His story is not just about laboratory breakthroughs; it's about a man whose enthusiasm for science was matched only by his generosity toward young scientists 2 .
The Hedgehog pathway functions like a master conductor in the orchestra of our body's development. It got its unusual name from fruit flies that, when the gene is mutated, develop spiky projections that resemble hedgehogs. In humans, this pathway plays critical roles during embryonic development, determining how cells grow, specialize, and organize themselves into proper structures 4 .
A Hedgehog protein binds to a receptor called Patched1 on the cell surface
This binding releases another protein called Smoothened from inhibition
Signals travel to the cell nucleus, activating Gli transcription factors
Gli factors turn specific genes on or off, directing cell behavior 4
They revealed how Gli proteins, the pathway's ultimate effectors, are controlled through acetylation and other modifications 2
They demonstrated that Hedgehog controls neural stem cells through regulation of Nanog, a key stem cell factor 4
They discovered that Hedgehog activation pushes cells to become dependent on aerobic glycolysis—a less efficient way of metabolizing sugar that cancer cells prefer
This "Warburg effect" gives cancer cells the building blocks they need to grow rapidly 4 .
Medulloblastoma, a devastating childhood brain cancer, often results from aberrant Hedgehog signaling. While several Hedgehog-inhibiting drugs had been developed, they primarily targeted Smoothened, the pathway's switch. Unfortunately, cancers often develop resistance to these drugs through mutations in components downstream of Smoothened 4 .
Gulino's team asked a revolutionary question: instead of directly targeting the Hedgehog pathway itself, could we target the metabolic processes that Hedgehog-activated cancer cells depend on? Specifically, they investigated whether inhibiting glycolysis (sugar metabolism) could starve these cancer cells 4 .
The findings were striking. When Hedgehog signaling was activated in normal GCPs:
| Treatment | Effect on Proliferation |
|---|---|
| SHH + Glucose | Massive stimulation (1500% of control) |
| SHH + Galactose | Markedly reduced (~300% of control) |
| SHH + 1mM DCA | Significant suppression (~800% of control) |
| SHH + 10mM DCA | Strong suppression (~400% of control) |
| SHH + 20mM DCA | Near-complete suppression (~200% of control) |
| Source: Adapted from research on Hedgehog-dependent metabolic reprogramming 4 | |
Additionally, the researchers found that Hedgehog signaling directly increased the expression of key glycolytic enzymes, and this effect could be blocked by inhibiting Gli transcription factors:
| Condition | HK2 mRNA Level | PKM2 mRNA Level |
|---|---|---|
| Control (no SHH) | Baseline | Baseline |
| SHH-treated | Significantly increased | Significantly increased |
| SHH + Arsenic Trioxide | No increase | No increase |
| Source: Adapted from research on Gli-dependent regulation of glycolytic enzymes 4 | ||
Different glycolysis inhibitors successfully blocked cancer cell growth:
| Inhibitor | Target | Effect on Proliferation |
|---|---|---|
| Dichloroacetate (DCA) | Pyruvate dehydrogenase kinase | Dose-dependent inhibition |
| 2-deoxyglucose (2DG) | Hexokinase | Strong inhibition |
| 3-Bromopyruvate (3-BrPA) | Hexokinase II | Strong inhibition |
| Source: Adapted from research on metabolic inhibition of Hedgehog-dependent tumors 4 | ||
This elegant experiment demonstrated that Hedgehog-dependent cancers become addicted to glycolysis, and that this addiction represents a promising therapeutic target. By attacking the cancer's energy supply rather than the signaling pathway itself, Gulino's team had potentially found a way to overcome the drug resistance that plagued existing treatments 4 .
Gulino's groundbreaking work relied on sophisticated laboratory tools and reagents that allowed his team to probe the inner workings of cancer cells.
| Reagent/Tool | Function in Research |
|---|---|
| SAG (Smoothened Agonist) | Artificial activation of Hedgehog pathway |
| Purmorphamine | Selective Smo activator targeting canonical pathway |
| Arsenic Trioxide (ATO) | Inhibitor of Gli transcription factors |
| Dichloroacetate (DCA) | Pyruvate dehydrogenase kinase inhibitor |
| 2-deoxyglucose (2DG) | Hexokinase inhibitor, blocks glycolysis |
| 3-Bromopyruvate (3-BrPA) | Potent hexokinase II inhibitor |
| Math1-Cre/Ptcfl/fl mice | Genetic model of medulloblastoma |
| Source: Compiled from research on Hedgehog pathway and cancer metabolism 4 | |
Alberto Gulino passed away on November 25, 2014, but his scientific legacy continues to influence cancer research today 1 2 . His work revealed not just the intricacies of cancer metabolism but also pointed toward novel therapeutic strategies that might be more effective and less prone to resistance than current approaches.
His approach—targeting the metabolic dependencies of cancer cells rather than just their signaling pathways—represents a paradigm shift in how we think about cancer treatment. The "sugar addiction" of Hedgehog-dependent cancers that Gulino identified could be exploited with drugs like DCA, which has the advantage of being already approved for certain metabolic disorders, potentially speeding its repurposing for cancer therapy 4 .
Beyond his specific discoveries, Gulino's greatest legacy may be the scientific culture he built. As director of the Laboratory of Molecular Oncology at Sapienza University, he fostered an environment where young scientists could thrive 2 . Former students remember how he would organize scientific events at "fantastic small hotel[s] facing Palazzo Farnese near Campo de' Fiori and Piazza Navona" where the science was so engaging that younger attendees complained it was "terrible" because they had no time for sightseeing 2 .
1952-2014
Italian molecular biologist whose work revealed cancer's metabolic vulnerabilities
Gulino's career exemplifies how passion for science, combined with rigorous investigation and generosity toward the next generation, can lead to breakthroughs that change our fundamental understanding of disease. His work on cancer metabolism continues to inspire researchers exploring new ways to starve cancers of their favorite foods, offering hope for more effective treatments for some of the most challenging childhood cancers 4 .
As we continue to build on his discoveries, we remember not just the scientist but the man—someone who loved both the intricacies of molecular pathways and the stories of Rome, told over dinner at "superb small local restaurants where he and his wife, Isabella Screpanti, were known by name by the owners and the cooks" 2 .