Nature's New Breakthrough: First Confirmation of the Origin of a Deadly Brain Tumor!

Scientists at St.
Judah's Children's Research Hospital have discovered which cells produce certain high-risk medulloblastoma populations
.
These findings will help researchers better understand the biology of the disease, as well as develop better research models and guide them in their search for therapeutic targets
.
The findings are published today in the
journal Nature.

Medulloblastoma is the most common malignant brain tumor
in children.
It has four molecular subgroups: SHH, WNT, Group 3 (Group 3) and Group 4 (Group 4
).
Studies have revealed which neural tissues produce SHH and WNT: SHH comes from the outer particle layer (where granular neurons grow), and WNT comes from the brainstem
.
However, the origin of groups 3 and 4 medulloblastoma is difficult to determine
.

Now, scientists have traced the developmental starting point of groups 3 and 4 of medulloblastoma, the rhombic lip, a structure
for early development of the cerebellum.
This is the first time researchers have identified the specific origin of group 3 medulloblastomas and reinforced previous discoveries
about group 4 medulloblastomas.

Dr Paul Northcott, corresponding author of the Department of Developmental Neurobiology in St.
Judas, said: "There is ambiguity and overlap between groups 3 and 4, which makes it challenging
to determine their origins.
" "We already have evidence that these groups have some sort of common ancestry and then possibly differentiate based on the genetic events that drive these tumors, but until now we haven't been able to definitively identify
.
"

"After helping to discover and describe Groups 3 and 4 more than a decade ago, my lab has been curious
to solve their developmental biology problems and figure out if they share a common ancestor.
"

Find the right map

In 2019, Northcott and his team released an atlas
of mouse cerebellar development.
The work relied on single-cell transcriptional profiling, allowing the researchers to compare the profiles
of medulloblastoma patients and mouse cerebellums.
Previous mouse atlas studies have shown that group 4 medulloblastomas originate from unipolar brush cells and can also be traced back to the developmental process
of the rhombus lips.
But the origin of group 3 medulloblastomas remains unclear
.

Northcott then collaborated with Dr.
Kathleen Millen of Seattle Children's Hospital on the study
.
Millen and her team created the first atlas
of human cerebellar development.
With the human genome map, Northcott and his team were able to look for transcriptome signatures
of different medulloblastoma subsets in the context of the same species.
Notably, the scientists found that both groups 3 and 4 may have come from rhomboid lips, one of the main regions of
the developing cerebellum.

"Once we have the human map, everything is turned on, and there are these obvious differences between human and mouse cerebellar development, which suggests that human development is much more
complex.
"

There was a cancerous detour on the road to development

Think of the rhombus lips as the starting line
of a race.
Stem cells and progenitor cells are aggregating, ready to take off
.
Once the cells begin their journey, they begin to differentiate, differentiating into different groups
of cells in different directions.

The researchers matched
these different cell populations from the rhomboid lips to groups 3 and 4 medulloblastomas.
Group 3 cells are more primitive (they are closer to the starting line), while Group 4 cells develop farther (they go farther at the starting line
).

The findings answer why groups 3 and 4 have some of the same characteristics, but are different
.
They arise in the same region, but come from different cell populations
on the trajectory of their development.

The findings also highlight the need to combine expertise from different disciplines for collaborative research
.
For example, in addition to transcriptomics analysis, the researchers also used imaging techniques to help with their research
.
Northcott and his team collaborated on this work with the late Dr.
Zoltán Patay, who at the time served as chair of the Department of
Diagnostic Imaging at St.
Judas.

Patay, one of the paper's authors, spoke of the study: "This work highlights the need and value
of dialogue and exchange of ideas between basic research scientists and clinical experts, including radiologists in research work.
This collaboration enables observational MRI results and basic research data to be synergistically validated with each other to determine the anatomical starting point
for these tumors in groups 3 and 4 of medulloblastoma.
This is a possibility
unique to St.
Judas.
”

In addition to answering an urgent biological question, these findings may help researchers design better models to study these subpopulations
.
Understanding cell origin will also allow researchers to compare blast cells and tumor cells for a more nuanced understanding of tumor-specific dependencies that can be explored
therapeutically.

essay

Rhombic lip implicated in origins of high-risk medulloblastoma