Pannexin 1 induces Rhabdomyosarcoma cell fusion by downregulating APOBEC2
Bibliographic record
Abstract
Rhabdomyosarcoma (RMS) is an aggressive cancer thought to arise from impaired myogenesis. This can be substantially overcome by increasing the levels of pannexin 1 (PANX1), a critical component of the myogenic program, but the mechanism involved is unknown. Using RNA-seq, we have previously found that overexpression of PANX1 dramatically reshapes the transcriptomic landscape of RMS including downregulation of a myogenic modulator, APOBEC2 (apolipoprotein B mRNA editing enzyme catalytic subunit 2). Following this clue, we investigated the role of APOBEC2 in the PANX1-mediated suppression of RMS malignancy. Here we show that, using a panel of patient-derived RMS cell lines and tumor specimens, APOBEC2 is expressed in RMS, but that its levels are lower than those in both differentiating myoblasts and skeletal muscle. In most RMS cell lines examined, APOBEC2 accumulates during proliferation and sustains their stem-like characteristics, as evidenced by its ability to promote the growth of spheroids upon increased expression. Yet, ectopic PANX1 expression led to a marked downregulation of APOBEC2 across a large proportion of RMS cell lines assessed. Strikingly, these were the same cells in which PANX1 triggers multinucleation. We further reveal that, like healthy myoblasts progressing through myogenesis, the multinucleation observed here in RMS cells results from cell fusion. Importantly, in RMS cells engineered to overexpress APOBEC2, PANX1 no longer enhances cell fusion, but its other anti-tumorigenic properties are still preserved. Collectively, our data indicate that PANX1 promotes RMS cell fusion by downregulating APOBEC2 expression, driving these tumor cells further into the myogenic program.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| 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) | 0.000 | 0.000 |
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 teacher head, 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".