Tumors are composed of proliferating cells that invade healthy tissue and grow over time. Even
though it is still unclear, it is a common opinion that the cells of origin should possess a
proliferative capacity (Blanpain, 2013; Visvader, 2011). Particularly for brain cancers, the
transition of neural progenitors to differentiated postmitotic neurons is considered irreversible in
physiological and pathological conditions. Therefore, postmitotic neurons have not been
considered as suitable cell of origin for brain cancer. Here, we show that neurons reprograming
may occur upon Shh activation leading to medulloblastoma (MB) formation in vivo. Human SHH
medulloblastoma (MB) is a brain tumor affecting adults and infants that is thought to originate
from cerebellar granule neuron progenitors. Notably, several groups have shown that Shh
pathway activation (SmoM2 overexpression) in mouse granule neuron progenitors is able to
induce Shh MB (Schuller et al., 2008; Z.-J. Yang et al., 2008). These progenitors are present in
infants and newborn mice, but they seem to be absent in adult humans and mice (Biran, Verney,
& Ferriero, 2012; Marzban et al., 2014; Z.-J. Yang et al., 2008). Furthermore, it was recently
discovered that the two different forms of SHH MB are distinguished by different
transcriptome/methylome levels suggesting that the adult SHH MB may originate from a different
cell of origin (Cavalli et al., 2017; Kool et al., 2014). Relying on these data, we take advantage of a
conditional Cre-Lox recombination system to recapitulate the human adult medulloblastoma
pathogenesis in mice, demonstrating that cerebellar post-migratory mature granule neurons upon
SmoM2 overexpression can dedifferentiate and give rise to SHH MB in vivo. Moreover, human
adult patients present inactivating mutations of the chromatin reader BRPF1 that are associated
with SMO mutations and absent in pediatric and adolescent patients. Here we found that
truncated BRPF1 protein, as found in human adult patients, is able to induce medulloblastoma in
adult mice upon SmoM2 activation. Notably, gene expression profiling on our samples allowed to
associate “cerebellar granule progenitors-derived MB” with the human infant form while
“truncated BRPF1-induced tumors” clustered with human adult SHH MB. Furthermore, as
previously described by Kool et al., 2014, human adult SHH MB is characterised by the copresence
of p-AKT and p-S6, compared to the human infant SHH MB that are positive for either p-
AKT or p-S6 and always in a mutually exclusive way. Truncated BRPF1-induced tumors are double
positive for p-AKT and p-S6, similarly to adult patients, while cerebellar granule progenitors
derived MB present only p-S6. Furthermore, to define the contribution of chromatin changes in
granule neurons dedifferentiation in response to Shh activation, we profiled changes in chromatin
accessibility by ATAC-seq analysis on mice cerebella. SmoM2 overexpression changed the
epigenetic landscape of granule neurons, enriching the number of open chromatin regions
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associated with stem/progenitor-like genes. Moreover, the cooperation between truncated
BRPF1 and SmoM2 in reshaping the chromatin arrangement of granule neurons was explored
applying ATAC-seq on differentiated human cerebellar neurons derived from neuroepithelial cells.
ATAC-seq analysis pointed out a synergistic mechanism between SmoM2 and truncated BRPF1 in
modifying the epigenetic landscape of postmitotic neurons, increasing the chromatin accessibility
of super-enhancers, associated with stemness and chromatin organization/modification genes.
Our novel model of cancer development could explain the human SHH medulloblastoma onset in
adult individuals where granule neuron progenitors are no more present. For these reasons, we
strongly believe that our model configures as an important starting point for a new field in cancer
and stem cell biology focusing on the study of mechanisms driving tumorigenesis in postmitotic
cells.
| Identifer | oai:union.ndltd.org:unitn.it/oai:iris.unitn.it:11572/262675 |
| Date | 22 May 2020 |
| Creators | Aiello, Giuseppe |
| Contributors | Aiello, Giuseppe, Tiberi, Luca |
| Publisher | Università degli studi di Trento, place:Trento |
| Source Sets | Università di Trento |
| Language | English |
| Detected Language | English |
| Type | info:eu-repo/semantics/doctoralThesis |
| Rights | info:eu-repo/semantics/openAccess |
| Relation | firstpage:1, lastpage:118, numberofpages:118 |
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