Hemangiosarcoma accounts for 1.3–2.8% of all canine malignancies and most commonly arises in the spleen, where it often grows silently until rupturing and causing life-threatening internal bleeding. The cancer’s ability to metastasize rapidly and resist treatment has left veterinarians and researchers searching for better ways to understand, and ultimately target, what makes this disease so relentless.
A recent study from researchers at Hokkaido University and Yale School of Medicine investigated something new: how hemangiosarcoma cells manage to survive when their fuel supply—glucose—runs low.
What they found challenges the way we think about cancer metabolism. When hemangiosarcoma cells run out of glucose, they don’t simply die. Instead, they activate a sophisticated survival program using lactate (a molecule long dismissed as a waste product) to modify their DNA and turn on specific genes. This process is called lysine lactylation, and the study showed it persists even when glucose and lactate are scarce.
The lactylation marks become concentrated at the transcription start sites of specific genes, including ATF4, a master regulator that helps cells handle stress, and ASNS, which allows cells to manufacture their own asparagine from glutamine. This ability to produce essential nutrients on demand helps explain how hemangiosarcoma cells keep themselves alive when starved. In fact, adding asparagine to starving cells modestly boosted their growth.
Perhaps even more striking, glucose-starved hemangiosarcoma cells don’t just help themselves, they also reshape their surroundings. They release signals that attract macrophages and reprogram them into an “M2-like” state that suppresses the immune system and supports tumor growth rather than attacking it. In tumor samples from canine patients, areas with low lactylation levels showed significantly more of these pro-tumor immune cells, confirming the laboratory findings.
These findings reveal that hemangiosarcoma cells are remarkably adaptable. When nutrients run low, they don’t passively wait to die—they actively reorganize their DNA, manufacture their own building blocks, and engineer a protective environment that helps them survive. Understanding these survival pathways could eventually lead to drugs that block them, potentially making the cancer far more vulnerable to existing treatments.
The study does have important limitations. All metabolic experiments were performed in cell cultures, which don’t fully capture the complexity of real tumors. Researchers were also unable to directly target lactylation without affecting other cellular processes, making it difficult to prove causation definitively. Whether these mechanisms extend to other cancer types remains unknown. Larger studies using actual tumor samples are needed to validate these findings.
Still, this discovery represents a significant step forward. By mapping exactly how hemangiosarcoma adapts to stress, researchers have identified new vulnerabilities that could someday be targeted for treatment and better outcomes for dogs.
