Abstract PR012: MYOD1L122R induces chemoresistance and elevates cancer stem cell programs through WNT11-ROR2-VANGL2 signaling in aggressive rhabdomyosarcoma
Bibliographic record
Abstract
Abstract Background: Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of childhood or adolescents. The spindle sclerosing (ss-RMS) subtype has the worst outcome of all RMS patients and often harbor recurrent mutation of Leucine 122 to Arginine within the DNA binding domain of the transcription factor MYOD1. To date, the molecular function of MYOD1L122Rremains largely unknown. Methods: Here, we create the first animal model of MYOD1L122R using transgenic zebrafish. We also used CRISPR-homology-directed-repair and dox-inducible systems to express MYOD1L122R in human RMS cells. These models, along with patient tumors and patient-derived xenografts, were assessed by RNA- and ChIP-sequencing, single-cell RNA and ATAC (assay for transposase-accessible chromatin) sequencing, and immunohistochemistry to identify direct targets and downstream pathways regulated by MYOD1L122R. We also discovered that MYOD1L122R activates non-canonical WNT signaling to elevate cancer stemness and to impart chemo- and radiation-resistance through molecular mechanism studies. Results: Utilizing transgenic zebrafish models, we uncovered that MYOD1L122R is not oncogenic by itself but requires RAS pathway activation to generate rhabdomyosarcoma, akin to known gene associations found in ss-RMS patients. Limiting dilution cell transplantation revealed that MYOD1L122R increased the numbers of tumor propagating cells in zebrafish tumors. We next showed that engineered MYOD1L122R human tumors also have increased numbers of TPCs and were refractory to standard of care VAC (vincristine, actinomycin, and cyclophosphamide) and gamma-irradiation. Indeed, scRNA- and scATAC-seq of patient and patient-derived xenografts confirmed the elevation of cancer stem cell programs within MYOD1L122R tumors. We next identified the shared and differential genomic regions bound by MYOD1L122R using whole-genome ChIP and RNA sequencing. Most notably, MYOD1L122R bound to new DNA binding motifs shared with the MYC oncoprotein and transcriptionally upregulated cancer stem cell programs through distal enhancers. Unexpectedly, MYOD1L122R also bound to shared genomic regions with normal MYOD1 at transcription start sites/promoters to regulate muscle specific gene expression. Mechanistic studies revealed that MYOD1L122R binds to regulatory elements of ROR2 (receptor tyrosine kinase like orphan receptor 2), activating its expression and turning on the non-canonical WNT11-ROR2-VANGL2 pathway to elevate cancer stemness and to drive chemo- and radiation- resistance. Conclusions: MYOD1L122R is an RMS modifying gene that elevates cancer stemness and promotes chemo- and radiation- resistance through epigenetic reprogramming and activation of non-canonical WNT signaling pathway. The discovery of ROR2 in MYOD1L122R RMS patients grants future evaluation of this protein as a therapeutic target in combination with current standard of care. Citation Format: Yun Wei, Luis Antonio Corchete Sanchez, Diego Antelo, Sabateeshan Mathavarajah, Shuze Wang, Alexander Daiki Weissman, Jihee Lee, Miguel N. Rivera, Esther Rheinbay, David M. Langenau. MYOD1L122R induces chemoresistance and elevates cancer stem cell programs through WNT11-ROR2-VANGL2 signaling in aggressive rhabdomyosarcoma [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 PR012.
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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) | 0.004 | 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".