A New Human Fetal Brain Atlas Decodes the Origin and Formation of Brain Cancer

The most common malignant childhood brain tumors are medulloblastomas (MBs). They are classified into four major subgroups. Three main groups originate from the cerebellum, and one is from the dorsal brainstem’s lower rhombic lip. To help understand the origins of cerebellar tumorigenesis, rodent models have found applications in research. Analysis of their molecular, cellular, and histological models has aided research growth in studying brain tumors.

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CT Scan of Child with Medulloblastoma

CT Scan of Child with Medulloblastoma

The human cerebellum, in contrast, has a 750-fold larger surface area, higher cell numbers, and greater foliar and lineage complexity than the mouse cerebellum. The reactivation of embryonic developmental programs, and the emergence of stem-like cell plasticity, have been linked to tumorigenesis and treatment resistance in various organ cancers, including MB.

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Researchers used unprecedented single-cell transcriptomics profiling of whole cells from freshly isolated human fetal cerebella to define cell identities, transitional cell state dynamics, and lineage trajectories during early human fetal cerebellar development. They then compared them to single-cell transcriptomes of MB subgroups to determine which developmental programs and cell populations are susceptible to tumor transformation.

The study gives a better understanding of brain tumors.

Previous investigations of cell types in mouse cerebella or human analogs from frozen tissue nuclei could not clearly describe the compositional variability of MBs. The developmental genesis and evolution of MB are still unknown. The researchers revealed that tumor-subtype-specific transitory states in MB categories connect transitional cerebellar progenitors (TCP) and tumor cell populations by intersecting cellular states across developing fetal cerebella and MB subgroups. Their result implies that TCP-like cells act as a transition state in these MB subgroups.

The study used a previously unseen single-cell profile of freshly isolated human embryonic cerebella at various developmental stages to create a reference map for distinguishing the hierarchical cellular states in MBs. Transcriptomic study of single cells in the human fetal cerebellum revealed previously unknown transitional intermediate progenitors. These cerebellar TCP cells are more during a brief period near the first-to-second-trimester transition.

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The transition stage is crucial for neuronal lineage specification, proliferation, and migration. There is a decline in TCP cells shortly after the transition. The findings shed light on the dynamics of cerebellar lineage changes and probable cell sources of aggressive MB, implying that TCP cells in the early human fetal cerebellum are prone to malignant transformation during MB carcinogenesis. The role of TCP in brain tumors allows for more research with human models.

Clinical significance

The findings shed light on the probable genesis, lineage flexibility, and human-specific nature of MB subtypes and their intra- and inter-tumoral variability in malignancy while suggesting a targetable vulnerability for aggressive MB therapeutic intervention. These find clinical application in developing better treatment options for the cancerous tissues in the brain.

Conclusion

Understanding the origin and formation of brain tumors, especially MB, can help scientists plan for better outcomes. The study also solved the limitations of the rodents’ models of research. With the findings of this new study with human models, previously unconsidered cells in the origin of MB are evident. The role of TCP previously not explained is seen with the new mapping of the fetal brain.

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References

Single-cell Atlas of Human Fetal Cerebellum Decoding Medulloblastoma Origin and Oncogenesis | bioRxiv

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