Abstract PR006: Activated ALK and MYCN drive neuroblastoma initiation through tissue-specific dynamics of neuroblast persistence and transformation
Nour El Houda Djerir, Amira Kramdi, Cécile Thirant, Cécile Pierre-Eugène, Renaud Leclere, Caroline Louis-Brennetot, Sakina Zaidi, Sylvain Baulande, Olivier Delattre, Isabelle Janoueix-LeroseyAbstract
Background
Neuroblastoma (NB) is an embryonal malignancy of the sympathetic nervous system that arises in either the adrenal gland or sympathetic ganglia. However, its developmental origin and the earliest steps of tumor initiation remain incompletely understood. We investigated how ALK activating mutations and MYCN overexpression cooperate during sympathoadrenal development to initiate tumorigenesis.
Methods
Histopathology, immunofluorescence, single-cell RNA sequencing (scRNA-seq), and spatial transcriptomics were used to characterize adrenal glands and ganglia-derived tumors from MYCN, activated ALK (aALK), and MYCN-aALK mouse models from postnatal development to adult stages.
Results
We first demonstrated that the abdominal tumors developing in MYCN-aALK mice originate from the celiac ganglia. In addition, we identified a second tumor site within the adrenal gland, despite the absence of macroscopic adrenal abnormalities. Histological analyses confirmed the presence of intra-adrenal neuroblastoma, and scRNA-seq showed that adrenal- and celiac-derived tumors share highly similar transcriptional profiles at P17 and P30. Analysis of adrenal glands revealed that ALK activation alone induces the transient postnatal persistence of intra-adrenal neuroblasts, a population normally absent in wild-type mice after birth. In contrast, MYCN overexpression alone does not alter adrenal medulla development. Although aALK and MYCN-aALK neuroblasts exhibit highly similar transcriptional profiles at early postnatal stages (P1–P4), neuroblasts ultimately disappear from aALK adrenal glands in the absence of MYCN. By contrast, combined ALK activation and MYCN overexpression promotes the progressive expansion of persisting neuroblasts and culminates in adrenal tumor formation. Comparative transcriptomic analyses identified postnatal day 10 as a critical transition point in MYCN-aALK adrenal glands, marked by increased MYCN expression, enrichment of MYCN target gene programs, enhanced proliferation, and extensive transcriptional reprogramming preceding overt tumor formation. In contrast, spatial transcriptomic analyses revealed that celiac-derived tumors already display an established tumor transcriptional program and pronounced spatial and transcriptional intratumoral heterogeneity as early as P5, indicating that oncogenic transformation occurs earlier in the celiac ganglia than in the adrenal gland.
Conclusions
Our findings support a model in which ALK activation creates a permissive developmental state by maintaining intra-adrenal neuroblasts beyond their normal developmental window, while MYCN overexpression subsequently drives their malignant transformation. These results provide new insight into the developmental origin of neuroblastoma and reveal distinct temporal trajectories of tumor initiation in adrenal and sympathetic ganglion tissues.
Citation Format:
Nour El Houda Djerir, Amira Kramdi, Cécile Thirant, Cécile Pierre-Eugène, Renaud Leclere, Caroline Louis-Brennetot, Sakina Zaidi, Sylvain Baulande, Olivier Delattre, Isabelle Janoueix-Lerosey. Activated ALK and MYCN drive neuroblastoma initiation through tissue-specific dynamics of neuroblast persistence and transformation [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Bridging Discovery and Clinical Impact in Pediatric Cancer; 2026 Sep 22-25; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(18_Suppl_1):Abstract nr PR006.