Fascinatingly, the relationship between BMP and natural retinoic acid is well established in NORMAL DEVELOPMENT, tipping cells between apoptosis and differentiation. This mechanism can seemingly be preserved in neuroblastoma CANCER CELLS and exploited to kill them! 🤯🤯 10/n

Remarkably, using single-cell RNA-seq and IF we found that BMP signaling activity is dramatically higher in disseminated neuroblastoma cells in patient bone marrow. This seems to explain the unusual clinical observation of site-specific drug activity! 🤯 9/n

Retinoic acid has other seemingly unique activities. For example, while it has little activity against established bulky tumors in vivo, it has been shown to clear metastatic cells from the bone marrow in patients. Could this paradox stem from differential BMP activity? 8/n

We then showed that amplifying BMP signaling activity (e.g. by adding exogenous BMP to cells) can potentiate the apoptosis/senescence cell fate choice upon exposure to retinoic acid. Blocking BMP tipped the cells towards differentiation, and a comparatively weaker response. 7/n

We performed a genome-wide CRISPR screen in a retinoic acid-treated hyper-responsive neuroblastoma cell line, finding that BMP signaling genes (ACVR1, BMP, SMAD, etc) were heavily affecting response to retinoic acid. 6/n

No. The hyper-responsive cell lines are predominantly undergoing either apoptosis or senescence, before (or in parallel with) differentiation... 5/n