Abstract B033: Single-nuclei profiling of LFS development reveals tumour susceptibility
Bibliographic record
Abstract
Abstract Li-Fraumeni Syndrome (LFS), caused by pathogenic germline Tp53 mutations, is a pediatric cancer predisposition disorder associated with markedly elevated risk of early-onset tumors, particularly rhabdomyosarcoma (RMS). Our study examined how developmental disruption may prime the tissues of LFS individuals for tumorigenesis. Single-nuclei RNA sequencing (snRNA-seq) was performed on RMS tumors, distal muscle from mice matched to RMS tumors, and cancer-free WT and LFS mouse muscle to define lineage-specific transcriptomic signatures of LFS-RMS. Embryonic limb buds were collected at embryonic days 10, 12, 14, and 16, subjected to snRNA-seq, and used to reconstruct developmental trajectories. These lineage-specific signatures were mapped back onto both WT and LFS embryonic lineages to determine whether oncogenic programs were detectable in utero and to identify the timing of their emergence. A stress-primed transcriptional program was identified as a defining feature of LFS tissues. This program distinguished precancer from postcancer states, becoming amplified in both RMS tumors and distal muscle matched to tumors. In LFS embryos, stage-specific alterations were observed in cell type proportions and maturation, including the emergence of unique myogenic and mesenchymal subpopulations absent in both WT embryos and postnatal muscle, reflecting developmental plasticity restricted to the LFS embryonic context. A lag in the transition to mature myogenic cells was detected at E14, preceded by a spike in the LFS stress-primed signature at E12 during windows of active lineage specification and proliferation. Pathway analyses of lineage-specific signatures indicated widespread dysregulation, with particularly strong changes in RNA-associated and developmental programs, further defining this stress-sensitive transcriptional state. These findings provide the first single-nuclei resolution map of embryogenesis in LFS and provide evidence that LFS-associated oncogenic programs are prenatally encoded. By linking altered lineage dynamics, developmental plasticity, and stress-primed transcriptional states to the emergence of RMS, this work establishes a developmental framework for understanding pediatric cancer predisposition. The results highlight potential windows for early detection and suggest opportunities to target embryonically primed programs for intervention in LFS. Citation Format: Ashby Kissoondoyal, Paula R. Quaglietta, Brianne Laverty, David Malkin. Single-nuclei profiling of LFS development reveals tumour susceptibility [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Cancer Evolution: The Dynamics of Progression and Persistence; 2025 Dec 4-6; Albuquerque, NM. Philadelphia (PA): AACR; Cancer Res 2025;85(23_Suppl):Abstract nr B033.
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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 | 0.000 |
| 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".