Banca de QUALIFICAÇÃO: GUSTAVO LOVATTO MICHAELSEN

Uma banca de QUALIFICAÇÃO de DOUTORADO foi cadastrada pelo programa.
STUDENT : GUSTAVO LOVATTO MICHAELSEN
DATE: 04/11/2025
TIME: 03:30
LOCAL: Auditório do ICe
TITLE:

Identification of High Plasticity Cells in Medulloblastoma and Their Association with Chromosomal Instability

KEY WORDS:

medulloblastoma, single-cell RNA-seq, chromosomal instability, cell states

PAGES: 27
BIG AREA: Ciências Biológicas
AREA: Biologia Geral
SUMMARY:

Chromosomal instability (CIN), is a hallmark of aggressive cancers like medulloblastoma (MB) and is correlated with poor prognosis, metastasis, and relapse. However, the cell states that drive these adverse outcomes are not necessarily those with the highest global CIN, but rather the ones with the right combination of copy number variations (CNVs) that confers a selective advantage for the steps of metastasis, while managing the associated costs. In this study, we investigated the relationship between CIN and the recently identified High-Plasticity Cell (HPC) state, a stem-like and proliferative subpopulation enriched in recurrent MB. Using single-cell RNA-sequencing data from primary MB samples, we applied consensus non-negative matrix factorization (cNMF) to deconvolve the tumor transcriptome, identifying ten core meta-programs. One meta-program (state eight) robustly recapitulated the HPC gene signature and was enriched for proliferative biological processes. We then quantified CIN at single-cell resolution using inferCNV, calculating the average proportion of the genome altered by balanced CNVs. Our analysis revealed that CIN ranged from 17% in state seven, to 38% in the highly unstable, developmentally-defined stem-like state five, whereas HPCs possess an intermediate CIN burden of 28%. Crucially, while HPCs did not harbor strictly exclusive CNVs, they were significantly associated for specific chromosomal alterations, including gains of chromosomes 4 and 12 and loss of chromosome 10 in the SHH subgroup, and gains of chromosome 4 in Group 4 MB. Finally, gene regulatory network analysis using the SCENIC tool revealed 17 regulons activated specific in HPCs, mainly the regulons belonging the the transcription factors MYBL1, REST and MYBL2. Genes regulated by MYBL1 and MYBL2 were related to proliferative biological processes, while genes regulated by REST were linked to differentiation and development processes. Altogether, these findings demonstrate that the aggressive HPC state is not defined by maximal genomic chaos, but by a distinct, intermediate level of CIN coupled with specific regulatory mechanisms and chromosomal gains and losses that may collectively confer a selective advantage for tumor plasticity and progression.

COMMITTEE MEMBERS:
Presidente - 1507794 - RODRIGO JULIANI SIQUEIRA DALMOLIN
Externo ao Programa - ***.610.854-** - ANDRE LUIS FONSECA FAUSTINO - UFRN
Externa à Instituição - DEISY MORSELLI GYSI