Abstract A020 MYCN overexpression biases human sympatho-adrenergic development towards progenitor cells causing neuroblastoma-like tumor xenografts
Bibliographic record
Abstract
Abstract Neuroblastoma (NB) is a developmental disorder in children, accounting for ∼10% of pediatric cancers and being the leading cause of cancer-related deaths in children under five. Originating along the developing sympathetic axis, typically in the adrenal medulla, NB is characterized by disrupted differentiation of neural crest cells (NCCs) into human sympatho-adrenergic progenitors (hSAPs). MYCN, a crucial member of the MYC oncogene family, is essential for neural progenitor cell self-renewal, migration, and neural fate maintenance during early development. Dysregulated MYCN expression is linked to NB initiation and progression, especially during hSAP development, though the exact mechanisms remain unclear. To elucidate the effects of MYCN overexpression on hSAP development and NB-like tumor formation, we utilized an in vitro pluripotent stem cell-based hSAP developmental model. MYCN amplification, present in 25-30% of NB cases, is linked to high-risk disease and poor outcomes. Although MYCN induces apoptosis via pro-apoptotic factor transcription and DNA damage, its impact on hSAP lineage differentiation remains unclear. Using single-cell RNA sequencing we identified distinct developmental subpopulations in MYCN-overexpressing cells, with some showing abnormal development. Survival varied by developmental stage, with selective depletion in bridging cells and CPCs/ECCs. MYCN-overexpressing populations exhibited elevated replicative stress signatures and upregulation of survival genes, including GSK3B and components of the PI3K-AKT-MTOR and MAPK pathways, crucial for cell proliferation and survival in NB progression. Xenograft experiments showed that MYCN-overexpressing cells formed tumors regardless of the developmental time point of implantation. However, tumors from multipotent NCCs (D16) and the hSAP developmental window (D27, 29, 31) exhibited transcriptome and epigenetic differences. Tumors from multipotent NCCs resembled sympathoblasts but lacked true NB tumor expression signatures. This suggests MYCN overexpression biases non-lineage-restricted NCCs toward the hSAP lineage. Our findings reveal that MYCN overexpression induces transcriptional features like those observed in NB within sympatho-adrenergic progenitors (SAPs). Overexpression of MYCN enhances the activity of pro-survival, proliferation, and DNA-replication stress-response signaling pathways, selectively enriching for SAPs while inducing the death of other developmental populations. Moreover, surviving SAPs can develop into NB-like tumors, which are highly dependent on MYCN signaling, when implanted into a mouse xenograft model, showing a shorter latency compared to mice injected with earlier neural crest precursors. These findings elucidate the intricate relationship between MYCN, developmental stages, and NB pathogenesis, highlighting the need for targeted therapeutic strategies. Citation Format: Stephane Van Haver, Sarah-Lee Bekaert, Jubierre Luz, Celine Everaert, Ines Fernandez Maestre, Katleen De Preter, Ting Zhou, Alex Kentsis, Lorenz Studer, Hiroyuki Shimada, Frank Speleman, Stephen Roberts. MYCN overexpression biases human sympatho-adrenergic development towards progenitor cells causing neuroblastoma-like tumor xenografts [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr A020.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".