Medulloblastoma is one of the most common malignant brain tumors in children, accounting for about 20% of pediatric central nervous system tumors. Current clinical treatments face two major challenges: radiotherapy and chemotherapy cause significant damage to the developing brains of infants and young children, while targeted drugs against the Sonic Hedgehog (SHH) signaling pathway frequently encounter drug resistance. This dilemma has led scientists to question whether SHH-type medulloblastoma (SHH-MB) might possess a "backup engine" independent of the canonical pathway to sustain its survival and growth.
A recent study published in Protein & Cell provides a clear answer. Huang Bo's team discovered that the immune molecule Siglec-15 drives tumor growth in SHH-MB through a novel "lysosomal pathway," offering a new therapeutic target to address drug resistance.
Siglec-15 is traditionally known as an immune checkpoint molecule, primarily located on the cell membrane where it inhibits T-cell function. However, this study revealed that within SHH-MB tumor cells, Siglec-15 is surprisingly abundant on lysosomes. "In biology, we often say 'structure determines function,' but the location within the cell often dictates function as well," commented 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 found that this abnormal localization relies on a precise transport mechanism: the Siglec-15 protein is modified with an "address tag" – mannose-6-phosphate (M6P). This tag is recognized by the intracellular "logistics protein" CI-MPR, which then dispatches Siglec-15 from the Golgi apparatus to the lysosomes. "We were surprised to find that tumor cells cleverly hijack the M6P system, normally used for transporting lysosomal enzymes," said Wang Zhenfeng, a co-author of the paper.
To delve deeper, the team systematically investigated Siglec-15's impact on lysosomal function. They discovered that after relocating to the lysosomal membrane, Siglec-15 begins its new role: it interacts with the lysosomal calcium ion channel TRPML1, triggering calcium release. This calcium signal acts like a switch, activating the key transcription factor TFEB, which then enters the nucleus and initiates a program of genes that promote tumor growth. The research also traced the origin of this pathway: in SHH-MB cells, the tryptophan metabolite kynurenine persistently activates the transcription factor AhR, which acts as the "commander" driving the high production of Siglec-15.
This series of discoveries not only maps out the complete "AhR-Siglec-15-TRPML1-TFEB" oncogenic signaling axis but also points to potential new treatment strategies. In animal models, inhibiting AhR or blocking Siglec-15's lysosomal localization significantly suppressed tumor growth without affecting the molecule's normal immune functions.
Shangxun Zhong, a PhD student at the Institute of Biophysics, remarked, "This research reveals how tumor cells utilize the lysosome as a signaling hub. However, the consequences of lysosomal calcium release likely extend beyond just the TFEB transcription factor." Zhong added, "Targeting the AhR-Siglec-15 axis could potentially bypass resistance to the canonical pathway, but subsequent clinical translation requires careful validation."
This work breaks new ground in understanding Siglec-15's functions, offering new hope and a potential direction for precision therapy for children facing limited treatment options.
DOI：10.1093/procel/pwaf100