A pioneering journey into cancer metabolism and the Hedgehog signaling pathway
Gulino's expertise in molecular pathways revealed cancer's hidden vulnerabilities
Known for his relational warmth and guidance of young scientists
Pioneered new approaches to target cancer metabolism
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 2 .
Gulino's 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. After training in Rome and Paris, and a research stint at the National Cancer Institute in Bethesda, USA, he returned to Italy, where he eventually became a full professor and dean of the Faculty of Medicine and Surgery 2 .
His most significant contributions revolved around understanding the Hedgehog signaling pathway—a crucial communication system in our cells that guides embryonic development but, when malfunctioning, can drive cancers like medulloblastoma, the most common childhood brain cancer 4 6 . Gulino discovered that this pathway forces cancer cells to undergo metabolic reprogramming, essentially making them sugar addicts—and that this addiction could be targeted with drugs. His work continues to influence how scientists approach cancer treatment today, even after his passing in 2014 1 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 6 .
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 discovered that a protein called Numb regulates Gli function, creating another layer of control 2
They found that microRNAs can regulate Hedgehog signaling, revealing yet another complexity 2
They demonstrated that Hedgehog controls neural stem cells through regulation of Nanog, a key stem cell factor 6
Perhaps most importantly, Gulino's team discovered that Hedgehog activation pushes cells to become dependent on aerobic glycolysis—a less efficient way of metabolizing sugar that cancer cells prefer even when oxygen is available. 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:
Proliferation increase in glucose conditions 4
Proliferation in galactose conditions 4
| Treatment | BrdU Incorporation (% of Control) | Effect on Proliferation |
|---|---|---|
| SHH + Glucose | 1500% | Massive stimulation |
| SHH + Galactose | ~300% | Markedly reduced |
| SHH + 1mM DCA | ~800% | Significant suppression |
| SHH + 10mM DCA | ~400% | Strong suppression |
| SHH + 20mM DCA | ~200% | Near-complete suppression |
| 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 |
| 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 |
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.
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 | Specific Example from Gulino's Work |
|---|---|---|
| SAG (Smoothened Agonist) | Artificial activation of Hedgehog pathway | Used to stimulate Hedgehog signaling in GCPs 4 |
| Purmorphamine | Selective Smo activator targeting canonical pathway | Demonstrated Gli-dependent metabolic effects 4 |
| Arsenic Trioxide (ATO) | Inhibitor of Gli transcription factors | Confirmed Gli-dependent regulation of glycolytic enzymes 4 |
| Dichloroacetate (DCA) | Pyruvate dehydrogenase kinase inhibitor | Suppressed Hedgehog-dependent tumor growth in vitro and in vivo 4 |
| 2-deoxyglucose (2DG) | Hexokinase inhibitor, blocks glycolysis | Inhibited Hedgehog-induced GCP proliferation 4 |
| 3-Bromopyruvate (3-BrPA) | Potent hexokinase II inhibitor | Blocked cancer cell growth by targeting glycolysis 4 |
| Math1-Cre/Ptcfl/fl mice | Genetic model of medulloblastoma | Provided tumor samples for studying metabolic reprogramming 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 .
Gulino fostered environments where young scientists could thrive
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. 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 .
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.
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 .