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Written by | Medulloblastoma
(MB), usually caused by cerebellar dysplasia, is a typical childhood malignancy
.
The cerebellum originates from the rhombic lip (RL) in the dorsal part of the posterior wing plate, an area responsible for generating all excitatory neurons that are then internalized into nodules
.
Anatomically, RL is separated by the vascular bed and divided into two parts: the ventricular zone (RL VZ) and the subventricular zone (RLSVZ).
There are four molecular subsets involved in MB, namely WNT, SHH, group 3 and group 4 [1].
。 Among them, WNT MBs originate from bryophytic fibrous neurons in the dorsal brainstem during the embryonic stage, while SHH and type 3/4 MB are thought to originate in the cerebellum
.
Type 3/4 MB accounts for 65% of clinical diagnoses, and MRI shows that it occupies most or all of the fourth ventricle, making it difficult for neuroscientists to track its origin
anatomically.
At the molecular level, the characteristics of type 3/4 MB are also unclear
.
Although the single-cell map of the developing mouse cerebellum has been depicted [2,3], it provides some opportunity
to infer the origin of different MB subtypes.
However, due to species differences, it is urgent to analyze the relationship between human cerebellar development and MB (especially 3/4 type MB) for the construction of accurate disease models and the formulation of clinical treatment plans.
Recently, Paul A.
Northcott's group from St.
Jude Children's Research Hospital and Kathleen J.
Millen's group from Seattle Children's Research Institute published a report in Nature titled Unified rhombic lip origins of group 3 and group 4 Medulloblastoma's article uses multiomics techniques to reveal the origin of the subpopulation of medulloblastoma during human cerebellar development and describe its molecular and phenotypic characteristics
.
The authors first used transcriptome data from 52,419 single cells and nuclei in the cerebellum of the human fetus (9-21 weeks after pregnancy) to map different molecular subsets of MB back to specific cell types
in cerebellar development at the bulk level.
SHH MB was found to be closer to the transcriptome of granule neuron progenitors (GNPs), type 3 MB corresponding to human embryonic RL, type 4 MB corresponding to RL, glutamatergic cerebellar nuclear neurons (glutamatergic).
cerebellar nuclear neuron) or unipolar brush cell (commonly referred to as GlutaCN/UBC because the two are difficult to distinguish
).
Subsequently, through quasi-temporal analysis, the authors found that type 3/4 MB cells fit well with early progenitor cells of the GlutaCN/UBC lineage, and type 4 MB cells have a higher
degree of differentiation.
Correspondingly, the results obtained by fitting MB subsets with cerebellar single-cell data were also consistent
.
To further confirm the relationship between type 3/4 MB and human RL–GlutaCN/UBC lineages, the authors microdissected RL samples and 7 external granule layer (EGL) samples from 7 human embryos (14-21 weeks' gestation) methylation was
mapped.
EGL acts as a transient germinal zone during cerebellar development, enriching a large number of proliferating GNPs
.
Methylation-based classification showed that all EGL samples were classified as SHH-MB, while RL pointed to type 3 MB, but the score of type 4 MB was low
.
The above conclusions comprehensively show that type 3/4 MB corresponds to GlutaCN/UBC lineage progenitor cells located in RL and differentiates
along this trajectory.
Subsequently, the authors introduced bulk RNA-seq datasets of human embryonic cerebellar subregions (subcompartments) to further refine the transcriptome atlas
.
The study found that RLVZ signaling was enriched in primitive RL cells in stem cell state, while RLSVZ signaling was more enriched in
progenitor cells with RL–GlutaCN/UBC development trajectories.
Subregion-specific gene set analysis of bulk MB expression profile also confirmed that SHH MB significantly enriched EGL expression characteristics, while type 3/4 MB significantly enriched RLSVZ characteristics
.
As expected, another gene set also showed significant enrichment of
UBC in the RLSVZ region.
Notably, the RLSVZ region identified photoreceptor signals
associated with the retina.
3.
Type 4 MB has different high-expression RLSVZ genes, type 3 MB expresses a large number of classical photoreceptor markers (such as EYS, GNB3, CRX, RPGRIP1), and type 4 MB highly expresses different UBC markers (such as EOMES, BARHL1, DDX31, LMX1A).
。 The immunostaining results of 43 patients' tumors were consistent with gene expression, with type 3 MB tumors expressing CRX and type 4 MB tumors expressing EOMES, and intermediate tumors expressing both, but the levels were relatively reduced
.
For decades, the origin of the photoreceptor expression characteristics of type 3 MB has been unclear [4-6].
In both the human embryonic cerebellum and MB, the authors observed a strong correlation
between the transcription factor OTX2 and the expression of RLSVZ photoreceptor signaling.
CRISPR–Cas9 gene editing experiments demonstrated that OTX2 is necessary for maintaining photoreceptor expression in type 3 MB and can inhibit glutamatergic neuron differentiation in MB
.
Next, in order to explore the genetic pathology of type 3/4 MB, the authors integrated the somatic mutation annotations of 324 cases of type 3/4 MB and found that GFI1B enhancer hijacking was significant in both subsets, which directly led to the BARHL1–DDX31 site Structural variation
(locus).
The hijacking frequency of BARHL1–DDX31 sites in type 3/4 MB is the same, and combined with the similarity of gene expression patterns in RLSVZ above, the authors believe that the use of multi-omics evaluation can better illustrate the origin
of RL in type 3/4 MB.
Combined with the evaluation of CHIP-seq, ATAC-seq, RNA-seq and methylation levels, the study found 3DDX31 transcription is active and chromatin is open in /4 MB, and DDX31 is mostly inactivated
in SHH MB.
In the GFI1B-activated 3/4 MB, the authors detected structural variation in the window of 4.
6 kb of the last intron of DDX31, and further found that the different methylation states of RL and EGL were relatively high methylation in SHH MB and human embryonic EGL samples, while both type 3/4 MB and human embryonic RL samples showed demethylation characteristics
.
Finally, the authors analyzed the atlases of 235,331 single cells in the mouse cerebellum and found that there was no enrichment of photoreceptor signaling from RLSVZ- in any cell type
.
Transcriptome analysis showed that Eomes in mice was mainly expressed in late-mitotic, metastatic and mature UBCs born in RL, while in the human brain, it was abundantly expressed in RLSVZ progenitor cells rather than more differentiated UBCs
.
All of the above shows that the cerebellar development of mice and humans varies greatly at the molecular level, and this study identified some human-specific characteristics
.
In addition, MRI of 'small MBs' showed different tumor localization for different
MB subtypes.
In general, this paper reveals the unknown lineage origin of type 3/4 MB, changes the previous perception that type 3 and 4 MB are completely independent entities, and describes its corresponding molecular signals, cell states, biological pathways and clinical phenotypes, and anatomical diagnostic sites, which are clinical MB Risk assessment and diagnosis (especially non-WNT/non-SHH MBs) provide guidance
.
During the same period, Michael D.
Taylor's team at The Hospital for Sick Children in Canada published back-to-back articles in Nature Failure of human rhombic lip differentiation underlies The medulloblastoma formation also reveals the important role
of labial differentiation in MB.
Pattern maker: Eleven
1.
Northcott, P.
A.
et al.
Medulloblastoma.
Nat.
Rev.
Dis.
Primers 5, 11 (2019).
2.
Hovestadt, V.
et al.
Resolving medulloblastoma cellular architecture by single-cellgenomics.
Nature 572, 74–79 (2019).
3.
Vladoiu, M.
C.
et al.
Childhood cerebellar tumours mirror conserved fetal transcriptionalprograms.
Nature 572, 67–73 (2019).
4.
Cho, Y.
J.
et al.
Integrative genomic analysis of medulloblastoma identifies a molecular subgroup that drives poor clinical outcome.
J.
Clin.
Oncol.
29, 1424–1430 (2011).
5.
Kool, M.
et al.
Integrated genomics identifies five medulloblastoma subtypes with distinct genetic profiles, pathway signatures and clinicopathological features.
PLoS One 3,e3088 (2008).
6.
Northcott, P.
A.
et al.
Medulloblastoma comprises four distinct molecular variants.
J.
Clin.
Oncol.
29, 1408–1414 (2011).
(MB), usually caused by cerebellar dysplasia, is a typical childhood malignancy
.
The cerebellum originates from the rhombic lip (RL) in the dorsal part of the posterior wing plate, an area responsible for generating all excitatory neurons that are then internalized into nodules
.
Anatomically, RL is separated by the vascular bed and divided into two parts: the ventricular zone (RL VZ) and the subventricular zone (RLSVZ).
There are four molecular subsets involved in MB, namely WNT, SHH, group 3 and group 4 [1].
。 Among them, WNT MBs originate from bryophytic fibrous neurons in the dorsal brainstem during the embryonic stage, while SHH and type 3/4 MB are thought to originate in the cerebellum
.
Type 3/4 MB accounts for 65% of clinical diagnoses, and MRI shows that it occupies most or all of the fourth ventricle, making it difficult for neuroscientists to track its origin
anatomically.
At the molecular level, the characteristics of type 3/4 MB are also unclear
.
Although the single-cell map of the developing mouse cerebellum has been depicted [2,3], it provides some opportunity
to infer the origin of different MB subtypes.
However, due to species differences, it is urgent to analyze the relationship between human cerebellar development and MB (especially 3/4 type MB) for the construction of accurate disease models and the formulation of clinical treatment plans.
Recently, Paul A.
Northcott's group from St.
Jude Children's Research Hospital and Kathleen J.
Millen's group from Seattle Children's Research Institute published a report in Nature titled Unified rhombic lip origins of group 3 and group 4 Medulloblastoma's article uses multiomics techniques to reveal the origin of the subpopulation of medulloblastoma during human cerebellar development and describe its molecular and phenotypic characteristics
.
The authors first used transcriptome data from 52,419 single cells and nuclei in the cerebellum of the human fetus (9-21 weeks after pregnancy) to map different molecular subsets of MB back to specific cell types
in cerebellar development at the bulk level.
SHH MB was found to be closer to the transcriptome of granule neuron progenitors (GNPs), type 3 MB corresponding to human embryonic RL, type 4 MB corresponding to RL, glutamatergic cerebellar nuclear neurons (glutamatergic).
cerebellar nuclear neuron) or unipolar brush cell (commonly referred to as GlutaCN/UBC because the two are difficult to distinguish
).
Subsequently, through quasi-temporal analysis, the authors found that type 3/4 MB cells fit well with early progenitor cells of the GlutaCN/UBC lineage, and type 4 MB cells have a higher
degree of differentiation.
Correspondingly, the results obtained by fitting MB subsets with cerebellar single-cell data were also consistent
.
To further confirm the relationship between type 3/4 MB and human RL–GlutaCN/UBC lineages, the authors microdissected RL samples and 7 external granule layer (EGL) samples from 7 human embryos (14-21 weeks' gestation) methylation was
mapped.
EGL acts as a transient germinal zone during cerebellar development, enriching a large number of proliferating GNPs
.
Methylation-based classification showed that all EGL samples were classified as SHH-MB, while RL pointed to type 3 MB, but the score of type 4 MB was low
.
The above conclusions comprehensively show that type 3/4 MB corresponds to GlutaCN/UBC lineage progenitor cells located in RL and differentiates
along this trajectory.
Subsequently, the authors introduced bulk RNA-seq datasets of human embryonic cerebellar subregions (subcompartments) to further refine the transcriptome atlas
.
The study found that RLVZ signaling was enriched in primitive RL cells in stem cell state, while RLSVZ signaling was more enriched in
progenitor cells with RL–GlutaCN/UBC development trajectories.
Subregion-specific gene set analysis of bulk MB expression profile also confirmed that SHH MB significantly enriched EGL expression characteristics, while type 3/4 MB significantly enriched RLSVZ characteristics
.
As expected, another gene set also showed significant enrichment of
UBC in the RLSVZ region.
Notably, the RLSVZ region identified photoreceptor signals
associated with the retina.
3.
Type 4 MB has different high-expression RLSVZ genes, type 3 MB expresses a large number of classical photoreceptor markers (such as EYS, GNB3, CRX, RPGRIP1), and type 4 MB highly expresses different UBC markers (such as EOMES, BARHL1, DDX31, LMX1A).
。 The immunostaining results of 43 patients' tumors were consistent with gene expression, with type 3 MB tumors expressing CRX and type 4 MB tumors expressing EOMES, and intermediate tumors expressing both, but the levels were relatively reduced
.
For decades, the origin of the photoreceptor expression characteristics of type 3 MB has been unclear [4-6].
In both the human embryonic cerebellum and MB, the authors observed a strong correlation
between the transcription factor OTX2 and the expression of RLSVZ photoreceptor signaling.
CRISPR–Cas9 gene editing experiments demonstrated that OTX2 is necessary for maintaining photoreceptor expression in type 3 MB and can inhibit glutamatergic neuron differentiation in MB
.
Next, in order to explore the genetic pathology of type 3/4 MB, the authors integrated the somatic mutation annotations of 324 cases of type 3/4 MB and found that GFI1B enhancer hijacking was significant in both subsets, which directly led to the BARHL1–DDX31 site Structural variation
(locus).
The hijacking frequency of BARHL1–DDX31 sites in type 3/4 MB is the same, and combined with the similarity of gene expression patterns in RLSVZ above, the authors believe that the use of multi-omics evaluation can better illustrate the origin
of RL in type 3/4 MB.
Combined with the evaluation of CHIP-seq, ATAC-seq, RNA-seq and methylation levels, the study found 3DDX31 transcription is active and chromatin is open in /4 MB, and DDX31 is mostly inactivated
in SHH MB.
In the GFI1B-activated 3/4 MB, the authors detected structural variation in the window of 4.
6 kb of the last intron of DDX31, and further found that the different methylation states of RL and EGL were relatively high methylation in SHH MB and human embryonic EGL samples, while both type 3/4 MB and human embryonic RL samples showed demethylation characteristics
.
Finally, the authors analyzed the atlases of 235,331 single cells in the mouse cerebellum and found that there was no enrichment of photoreceptor signaling from RLSVZ- in any cell type
.
Transcriptome analysis showed that Eomes in mice was mainly expressed in late-mitotic, metastatic and mature UBCs born in RL, while in the human brain, it was abundantly expressed in RLSVZ progenitor cells rather than more differentiated UBCs
.
All of the above shows that the cerebellar development of mice and humans varies greatly at the molecular level, and this study identified some human-specific characteristics
.
In addition, MRI of 'small MBs' showed different tumor localization for different
MB subtypes.
In general, this paper reveals the unknown lineage origin of type 3/4 MB, changes the previous perception that type 3 and 4 MB are completely independent entities, and describes its corresponding molecular signals, cell states, biological pathways and clinical phenotypes, and anatomical diagnostic sites, which are clinical MB Risk assessment and diagnosis (especially non-WNT/non-SHH MBs) provide guidance
.
During the same period, Michael D.
Taylor's team at The Hospital for Sick Children in Canada published back-to-back articles in Nature Failure of human rhombic lip differentiation underlies The medulloblastoma formation also reveals the important role
of labial differentiation in MB.
Original link:
https://doi.
org/10.
1038/s41586-022-05208-9
https://doi.
org/10.
1038/s41586-022-05215-w
Pattern maker: Eleven
References
1.
Northcott, P.
A.
et al.
Medulloblastoma.
Nat.
Rev.
Dis.
Primers 5, 11 (2019).
2.
Hovestadt, V.
et al.
Resolving medulloblastoma cellular architecture by single-cellgenomics.
Nature 572, 74–79 (2019).
3.
Vladoiu, M.
C.
et al.
Childhood cerebellar tumours mirror conserved fetal transcriptionalprograms.
Nature 572, 67–73 (2019).
4.
Cho, Y.
J.
et al.
Integrative genomic analysis of medulloblastoma identifies a molecular subgroup that drives poor clinical outcome.
J.
Clin.
Oncol.
29, 1424–1430 (2011).
5.
Kool, M.
et al.
Integrated genomics identifies five medulloblastoma subtypes with distinct genetic profiles, pathway signatures and clinicopathological features.
PLoS One 3,e3088 (2008).
6.
Northcott, P.
A.
et al.
Medulloblastoma comprises four distinct molecular variants.
J.
Clin.
Oncol.
29, 1408–1414 (2011).
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