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Neuroblastoma represents a challenging type of cancer that primarily affects children. The prognosis for patients classified as high-risk is notably poor. Historically, the incorporation of retinoic acid into neuroblastoma treatment regimens has led to a modest increase in survival rates by 10-15%. This enhancement, however, was observed only during the post-chemotherapy consolidation phase, following the significant reduction of bulky primary tumors. For nearly five decades, the underlying reasons for retinoic acid’s efficacy in this context, contrasted with its limited effectiveness against primary tumors, has remained a topic of speculation. Recent research conducted by scientists at St. Jude Children’s Research Hospital has shed light on this long-standing enigma, revealing that retinoic acid employs a unique mechanism to induce cell death in metastatic neuroblastoma. The drug effectively “hijacks” a natural developmental pathway to achieve its outcomes. These groundbreaking findings have important implications for future combination therapies and were published in Nature Communications.
“We have provided clarity on a puzzling contradiction that has persisted for decades regarding the effectiveness of retinoic acid during post-chemotherapy consolidation versus its minimal impact on primary neuroblastoma tumors,” stated senior co-corresponding author Paul Geeleher, PhD, from the St. Jude Department of Computational Biology. “The drug’s efficacy is significantly influenced by the cellular microenvironment.”
The cellular microenvironment comprises a complex mixture of chemicals, proteins, and various signals surrounding a cell, tailored to specific tissues. For instance, the bone marrow microenvironment contains signals that promote blood cell development and bone remodeling. Metastasized neuroblastoma cells often relocate to the bone marrow, where signaling through the bone morphogenetic protein (BMP) pathway is particularly pronounced. The research team demonstrated that this BMP signaling pathway renders neuroblastoma cells far more susceptible to the effects of retinoic acid.
“To our surprise, we discovered that neuroblastoma cells expressing genes associated with the BMP signaling pathway exhibited a high sensitivity to retinoic acid,” explained Min Pan, PhD, co-first and co-corresponding author from the St. Jude Department of Computational Biology. “This provided a clear rationale for why retinoic acid proves effective for treating cells in the bone marrow during consolidation therapy, while showing limited success against primary tumors during initial treatment.”
Leveraging Developmental Pathways to Induce Death in Metastatic Neuroblastoma Cells
Utilizing advanced gene-editing techniques, the researchers delved into the interplay between BMP signaling and retinoic acid. They established a set of neuroblastoma cell lines sensitive to retinoic acid, then systematically removed some genes to identify those responsible for the drug’s effects. Significant impacts were observed from genes in the BMP pathway, providing an explanation for the variable efficacy of retinoic acid observed in patients.
“Our research indicated that in neuroblastoma, BMP signaling interacts with retinoic acid signaling similarly to how they do during normal developmental processes,” remarked Yinwen Zhang, PhD, co-first author from the St. Jude Department of Computational Biology. Zhang elaborated on how specific transcription factors—proteins that bind to DNA to regulate gene expression—lead to differing reactions in neuroblastoma cells that are either highly sensitive or resistant to retinoic acid. “When numerous transcription factors associated with the BMP signaling pathway are present on the DNA, retinoic acid signaling synergizes with them to enhance the expression of genes linked to cell death. This mechanism is evident both in normal embryonic development and in neuroblastoma cells situated within specific microenvironments.”
“Our findings represent the first instance of identifying a ‘hijacking’ of a normal embryonic development process that can be harnessed for therapeutic purposes in cancer,” Geeleher stated. “This paves the way for investigating similar processes in other conditions to formulate treatment strategies that are both more effective and less toxic.”
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