Single-cell transcriptomics identifies potential cells of origin of MYC rhabdoid tumors

Abstract

Rhabdoid tumors (RT) are rare and highly aggressive pediatric neoplasms. Their epigenetically-driven intertumoral heterogeneity is well described; however, the cellular origin of RT remains an enigma. Here, we establish and characterize different genetically engineered mouse models driven under the control of distinct promoters and being active in early progenitor cell types with diverse embryonic onsets. From all models only Sox2-positive progenitor cells give rise to murine RT. Using single-cell analyses, we identify distinct cells of origin for the SHH and MYC subgroups of RT, rooting in early stages of embryogenesis. Intra- and extracranial MYC tumors harbor common genetic programs and potentially originate from fetal primordial germ cells (PGCs). Using PGC specific Smarcb1 knockout mouse models we validate that MYC RT originate from these progenitor cells. We uncover an epigenetic imbalance in MYC tumors compared to PGCs being sustained by epigenetically-driven subpopulations. Importantly, treatments with the DNA demethylating agent decitabine successfully impair tumor growth in vitro and in vivo. In summary, our work sheds light on the origin of RT and supports the clinical relevance of DNA methyltransferase inhibitors against this disease.

Aberrant DNA methylation distorts developmental trajectories in atypical teratoid/rhabdoid tumors

“…Based on our results, the temporal relationship to the DNA demethylation might be one of the key determinants of the cell fate after SMARCB1 inactivation. This is supported by recent findings that AT/RTs respond well to DNA methyltransferase inhibition both in vitro and in vivo ( Steinbügl et al, 2021 ; Graf et al, 2022 ). Further research will show if this or similar therapeutic approaches could benefit patients suffering from this devastating disease.…”

Three-Dimensional Cell Culture Systems in Pediatric and Adult Brain Tumor Precision Medicine

“…In this model, only early neuronal progenitor cells had the capacity to transform into tumor cells [ 52 ], which hinted at the progenitor cells being the potential cells of origin for this tumor entity. This finding in organoids recapitulates current findings in mice, in which only defined cells of origin and differentiation states give rise to ATRT development when Smarcb1 or Smarca4 is lost [ 31 , 96 , 97 , 98 ].…”

“…Despite making progress on exploring the mechanisms leading to tumor initiation by identifying, for example, (I) the mutational burden of tumors, (II) malignancies’ cells of origin, and (III) the impact of the TME on tumor cells [ 31 , 32 , 33 , 34 ], many key scientific questions to finally improve brain tumor patients’ survival remain unanswered. This lack of fundamental insight may partly stem from in vitro models insufficiently recapitulating the core characteristics of the primary tumors.…”

Single-cell analysis of peripheral blood from high-altitude pulmonary hypertension patients identifies a distinct monocyte phenotype

“…The co-culture experiment of the T cells and smooth muscle cells was carried out as in previous publication 49 . The PASMCs were seeded at 1 × 10 4 cells per well with complete medium in 96-well plate and incubated at 37 °C with 5% CO 2 for 24 h. The cells were then serum starved in DMEM/F12 for another 24 h. Culture supernatants were discarded and replaced with si CD28 or si Control transfected Jurkat Clone E6-1 T cells supplemented with 0.5% FBS and incubated at 37 °C with 5% CO 2 for 48 h. Cell viability was measured with MTT (3-(4,5-dimethylthiazol-2-yl)−2,5-diphenyltetrazolium bromide) assay as described previously 50 .…”