Scientists have identified a previously unknown lysosomal signalling pathway that drives growth in drug-resistant SHH medulloblastoma, which could lead to more precise and less harmful treatments for children with aggressive brain tumours.
Medulloblastoma is one of the most common malignant brain tumours in children, accounting for around 20 percent of paediatric central nervous system tumours. Despite progress in care, current clinical treatments face major challenges. Both radiotherapy and chemotherapy cause significant and lasting damage to the developing brains of infants and young children, while targeted drugs aimed at the Sonic Hedgehog signalling pathway often encounter drug resistance.
These limitations have prompted scientists to ask whether Sonic Hedgehog-type medulloblastoma (SHH-MB) might possess a ‘backup engine’ that allows it to survive and grow independently of the canonical pathway targeted by existing therapies.
Now, a new study has discovered that the immune molecule Siglec-15 drives tumour growth in SHH-MB through a previously unrecognised ‘lysosomal pathway’, opening a potential new therapeutic target for overcoming drug resistance.
An immune molecule with an unexpected role
Siglec-15 has traditionally been understood as an immune checkpoint molecule, primarily located on the cell membrane where it suppresses T-cell function. However, the new research revealed that in SHH-MB tumour cells, Siglec-15 is unexpectedly abundant on lysosomes, structures within cells that are best known for breaking down waste materials.
Siglec-15 has traditionally been understood as an immune checkpoint molecule, primarily located on the cell membrane where it suppresses T-cell function.
“In biology, we often say ‘structure determines function,’ but the location within the cell often dictates function as well,” said Dr Ziqi Xiao from the Institute of Biophysics. “When a key molecule appears in an unconventional location, it usually signifies a new task.”
The team discovered that this unusual localisation depends on a precise transport mechanism. The Siglec-15 protein is modified with an ‘address tag’ known as mannose-6-phosphate. This tag is recognised by an intracellular ‘logistics protein’ called CI-MPR, which dispatches Siglec-15 from the Golgi apparatus to the lysosomes.
A new study reveals the mechanism of SHH-MB tumour growth. (Figure source: Created using BioRender) Credit: HIGHER EDUCATON PRESS.[/caption] A newly identified cancer signalling axis
Further investigation demonstrated how Siglec-15 contributes to tumour progression once it reaches the lysosomal membrane. There, it interacts with the lysosomal calcium ion channel TRPML1, triggering the release of calcium. This increase in calcium acts as a molecular switch, activating the transcription factor TFEB. TFEB then enters the nucleus and switches on a programme of genes that promote tumour growth.
The researchers also traced the origin of this signalling cascade. In SHH-MB cells, the tryptophan metabolite kynurenine persistently activates the transcription factor AhR, which serves as the ‘commander’ driving high levels of Siglec-15 production.
Together, these findings map out what the team describe as the ‘AhR-Siglec-15-TRPML1-TFEB’ oncogenic signalling axis and highlight several potential intervention points.
Potential path towards new treatments
Encouragingly, experiments in animal models showed that inhibiting AhR or blocking the lysosomal localisation of Siglec-15 significantly suppressed tumour growth, without disrupting the molecule’s normal immune functions.
This research reveals how tumour cells utilise the lysosome as a signalling hub.
“This research reveals how tumour cells utilise the lysosome as a signalling hub. However, the consequences of lysosomal calcium release likely extend beyond just the TFEB transcription factor,” said Shangxun Zhong, a PhD student at the Institute of Biophysics. “Targeting the AhR-Siglec-15 axis could potentially bypass resistance to the canonical pathway, but subsequent clinical translation requires careful validation.”
The study develops science’s understanding of the diverse functions of Siglec-15 and could offer children with limited treatment options new therapies in the future. By identifying an alternative pathway that fuels tumour growth, researchers may have found a new direction for precision therapies in paediatric brain cancer.
