The group of Dr. Shicheng Su reveals that choroid plexus mast cells drive tumor-associated hydrocephalus
Source：Shicheng Su
2024-02-29
On December 21, 2023, the team of Dr. Shicheng Su from Sun Yat-sen Memorial Hospital, Sun Yat-sen University, published "Choroid plexus mast cells drive tumor-associated hydrocephalus" in Cell. The researchers identify a unique subset of choroid plexus-residing mast cells, which disrupt cilia of choroid plexus epithelium and promote tumor-associated hydrocephalus via tryptase.
Recent epidemiologic studies show that brain metastases afflict approximately 20-30% of patients with cancer, compared with 8-10% at the end of the 20th century. Despite its rapidly rising incidence and progressive development of treatments, its prognosis remains notoriously dismal. Intracranial hypertension is one of the leading causes of death in patients with brain tumors. Tumor-associated hydrocephalus, a common complication of intracranial malignancy, can dramatically increase intracranial pressure. However, underlying mechanisms are largely unknown due to an in vivo model of communicating TAH is lacking.
Researchers adopted a selection strategy to enrich cancer cells that cause TAH. Tumor cells were injected into the internal carotid artery. Brain metastatic cells were isolated from mice that developed ventriculomegaly and re-injected. After 3-4 rounds of selections, brain metastatic cells isolated from mice with ventriculomegaly were defined as VM cells. Those in mice without ventriculomegaly after equal numbers of selections were termed as unVM cells. Mice bearing VM cells exhibited significantly more ventricular volumes, stronger asymmetrical papilledema with blurred edges, higher intracranial pressure, dramatic decline on neurological and cognitive outcome and much poorer overall survival compared with normal mice and those inoculated with unVM cells. Moreover, VM-bearing mice showed markedly higher rates of CSF production, which was further identified as the main cause of the ventricular dilation in the communicating TAH model.
Researchers found the mast cells located in the choroid plexus exhibited the highest elevation in EO771-VM-bearing mice through single-nucleus RNA-sequencing (snRNA-seq) and spatial transcriptomics. Interestingly, snRNA-seq and flow cytometric analysis showed that choroid plexus mast cells (CPMCs) barely expressed high affinity immunoglobulin epsilon receptor subunit alpha (FcεRIα), a conventional marker of peripheral mast cells. IgE-mediated-activation of mast cells plays an important role in peripheral organs such as the lungs and peritoneum. Therefore, future efforts combining hematopoietic fate mapping experiments will be required to elucidate the origin and turnover of CPMCs.
Researchers validated the significant increase of CPMCs in mice with communicating TAH through 3D visualization of the intact choroid plexus, immunofluorescence, and flow cytometric analysis. Moreover, decreased brain ventricular volume, alleviated papilledema, diminished intracranial pressure, reduced CSF production and improved survival were observed in mast cell-deficient mice (Sash) mice compared with wild-type littermates. Loss of cilia on choroid plexus epithelium is associated with severe hydrocephalus. Through intracranial mast cell-specific Tpsb2 knockout mice, researchers found that tryptase secreted by CPMCs inhibits forkhead box J1 (FoxJ1) via proteinase-activated receptor 2 (PAR2) and consequently impairs cilia.
Immunofluorescence analysis unambiguously demonstrated the presence of tryptase+ cells in choroid plexus of human brains, indicating humans also harbor CPMCs. Furthermore, levels of tryptase in CSF were closely correlated with the Evan’s score, which is an indicator of hydrocephalus in 134 patients with brain metastases. BMS-262084 is a small molecular inhibitor of tryptase. Daily intraperitoneal injection of BMS-262084 increased number and length of choroid plexus epithelia cilia in both VM-bearing mice and a pluripotent stem cell-derived organoid model. Furthermore, BMS-262084 treatment ameliorated hydrocephalus, improved neurological and cognitive outcome and prolonged survival of mice inoculated with VM cells.
Collectively, this study uncovers for the first time the function of CPMCs located in a neuroimmunological border, and provides an attractive therapy for communicating TAH.
Links: https://www.cell.com/cell/fulltext/S0092-8674(23)01182-0
Recent epidemiologic studies show that brain metastases afflict approximately 20-30% of patients with cancer, compared with 8-10% at the end of the 20th century. Despite its rapidly rising incidence and progressive development of treatments, its prognosis remains notoriously dismal. Intracranial hypertension is one of the leading causes of death in patients with brain tumors. Tumor-associated hydrocephalus, a common complication of intracranial malignancy, can dramatically increase intracranial pressure. However, underlying mechanisms are largely unknown due to an in vivo model of communicating TAH is lacking.
Researchers adopted a selection strategy to enrich cancer cells that cause TAH. Tumor cells were injected into the internal carotid artery. Brain metastatic cells were isolated from mice that developed ventriculomegaly and re-injected. After 3-4 rounds of selections, brain metastatic cells isolated from mice with ventriculomegaly were defined as VM cells. Those in mice without ventriculomegaly after equal numbers of selections were termed as unVM cells. Mice bearing VM cells exhibited significantly more ventricular volumes, stronger asymmetrical papilledema with blurred edges, higher intracranial pressure, dramatic decline on neurological and cognitive outcome and much poorer overall survival compared with normal mice and those inoculated with unVM cells. Moreover, VM-bearing mice showed markedly higher rates of CSF production, which was further identified as the main cause of the ventricular dilation in the communicating TAH model.
Researchers found the mast cells located in the choroid plexus exhibited the highest elevation in EO771-VM-bearing mice through single-nucleus RNA-sequencing (snRNA-seq) and spatial transcriptomics. Interestingly, snRNA-seq and flow cytometric analysis showed that choroid plexus mast cells (CPMCs) barely expressed high affinity immunoglobulin epsilon receptor subunit alpha (FcεRIα), a conventional marker of peripheral mast cells. IgE-mediated-activation of mast cells plays an important role in peripheral organs such as the lungs and peritoneum. Therefore, future efforts combining hematopoietic fate mapping experiments will be required to elucidate the origin and turnover of CPMCs.
Researchers validated the significant increase of CPMCs in mice with communicating TAH through 3D visualization of the intact choroid plexus, immunofluorescence, and flow cytometric analysis. Moreover, decreased brain ventricular volume, alleviated papilledema, diminished intracranial pressure, reduced CSF production and improved survival were observed in mast cell-deficient mice (Sash) mice compared with wild-type littermates. Loss of cilia on choroid plexus epithelium is associated with severe hydrocephalus. Through intracranial mast cell-specific Tpsb2 knockout mice, researchers found that tryptase secreted by CPMCs inhibits forkhead box J1 (FoxJ1) via proteinase-activated receptor 2 (PAR2) and consequently impairs cilia.
Immunofluorescence analysis unambiguously demonstrated the presence of tryptase+ cells in choroid plexus of human brains, indicating humans also harbor CPMCs. Furthermore, levels of tryptase in CSF were closely correlated with the Evan’s score, which is an indicator of hydrocephalus in 134 patients with brain metastases. BMS-262084 is a small molecular inhibitor of tryptase. Daily intraperitoneal injection of BMS-262084 increased number and length of choroid plexus epithelia cilia in both VM-bearing mice and a pluripotent stem cell-derived organoid model. Furthermore, BMS-262084 treatment ameliorated hydrocephalus, improved neurological and cognitive outcome and prolonged survival of mice inoculated with VM cells.
Collectively, this study uncovers for the first time the function of CPMCs located in a neuroimmunological border, and provides an attractive therapy for communicating TAH.
Links: https://www.cell.com/cell/fulltext/S0092-8674(23)01182-0
