Abstract B005: BMP signaling determines neuroblastoma sensitivity to retinoic acid by directing cell fate
Bibliographic record
Abstract
Abstract Retinoic acid (RA) is a standard-of-care neuroblastoma drug used during post-chemo consolidation therapy. Based on clinical trials from the 90s, RA benefits 10-15% of patients. It is widely believed the anti-cancer activity of RA is due to retinoid-induced differentiation of cancer cells, conclusions largely attributable to observations in cell culture. However, given RA is typically used in the minimal residual disease setting, this mechanism has never been definitively proved in patients. To better understand RA’s activity, we deployed several new technologies. First, we conducted genome-wide CRISPR modifier screens in RA-treated hyper-sensitive neuroblastoma cell lines. Surprisingly, we found that, in these cells, RA primarily decreased cell viability via apoptosis or senescence, rather than differentiation—activities in which the CRISPR screens strongly implicated bone morphogenetic protein (BMP) signaling. Using ChIP-seq and RNA-seq we showed these behaviors were mediated by the coordinated gene regulatory actions of RARA and BMP-family SMAD transcription factors. Notably, interactions between BMP signaling and RA are well established in developmental biology, where BMP signaling can tip cell fate decisions between differentiation, apoptosis, and senescence upon exposure to naturally occurring RA, behaviors that can seemingly be maintained in neuroblastoma cells. Next, we assessed the correlations between RA IC50 and the expression of all (∼20,000) genes in a panel of 19 cell lines. Remarkably, SMAD9, a critical downstream transcription factor of the BMP pathway, was the #1 most correlated gene with RA IC50 (R = -0.92, P = 4.2 × 10-6), suggesting a highly generalizable relationship between BMP signaling and RA response. By modulating SMAD9, or other components of BMP signaling, we could promote apoptosis/senescence and sensitize cells to RA. We then performed large-scale drug combination screens of RA and the drug FK506, which can amplify BMP signaling activity. RA exhibited a synergistic effect with FK506 in all 10 neuroblastoma cell lines we tested, very strikingly in some cases, suggesting it could be possible to pharmacologically amplify the activity of RA in patients. Finally, using published single-cell RNA-seq data from neuroblastoma patient samples, we found BMP signaling activity is relatively low in primary tumors, but much higher in disseminated metastatic neuroblastoma cells in the bone marrow. We confirmed this trend using immunofluorescence staining in 6 paired primary patient samples. This site-specific variability in BMP signaling activity provides the first reasonable explanation for RA’s curious clinical activity, whereby it has little effect on bulky established tumors, but has been shown to clear disseminated metastatic cells from the bone marrow during consolidation therapy. Overall, our study revealed that BMP signaling controls neuroblastoma cell fate and sensitivity to RA and that this observation is consistent with the unique clinical behaviors of this drug. Citation Format: Min Pan, Yinwen Zhang, William C. Wright, Hyeong-Min Lee, Richard H. Chapple, Xueying Liu, Jonathan Low, Duane Currier, Allister J. Loughran, Michael A. Dyer, Shondra M. Pruett, Burgess Freeman III, Taosheng Chen, Brian J. Abraham, Elizabeth Stewart, John Easton, Paul Geeleher. BMP signaling determines neuroblastoma sensitivity to retinoic acid by directing cell fate [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 B005.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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 | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.006 | 0.002 |
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".