Single gene-pair loss explains how the same tumor type can look completely different — including across neuroblastoma and paraganglioma

Single gene-pair loss explains how the same tumor type can look completely different — including across neuroblastoma and paraganglioma

Neuroblastoma and paraganglioma are both cancers arising from the sympathoadrenal lineage (cells near the adrenal gland), yet they can appear quite different. How they're related developmentally and why they're so heterogeneous has been unclear.

Using a mouse model with combined loss of KIF1Bβ (a chromosome 1p36 tumor suppressor gene) and NF1, researchers found this gene combination drives extensive cell-state reprogramming within the sympathoadrenal lineage. Single-cell transcriptomics revealed these tumors can shift between chromaffin-like states (characteristic of paraganglioma) and neuroblast-like states, passing through developmental intermediates. Spatial transcriptomics showed these transitions happening within spatially distinct tumor zones.

The result: the same initial genetic event (KIF1Bβ + NF1 loss) can produce a spectrum of tumor types — paraganglioma, neuroblastoma, or composite mixed tumors — depending on where the cell-state reprogramming lands. This fundamentally changes how we think about intratumoral heterogeneity in these cancers.

Key Findings

• Loss of KIF1Bβ and NF1 together drives cell-state reprogramming in the sympathoadrenal lineage
• This reprogramming gives rise to paraganglioma, neuroblastoma, and composite tumors from the same genetic event
• Single-cell transcriptomics revealed chromaffin-to-neuroblast reprogramming through developmental intermediates
• Spatial transcriptomics confirmed spatially distinct tumor zones with different cell states
• KIF1Bβ is identified as a 1p36 candidate tumor suppressor cooperating with NF1 in tumorigenesis

Implications

These findings clarify the developmental relationship between paraganglioma and neuroblastoma and explain how intratumoral heterogeneity arises. For clinicians, this suggests that tumor biopsies from different regions may need different treatments, and that tracking cell-state transitions could inform prognosis and therapeutic strategy.

Caveats

Preprint, not peer reviewed. Mouse model findings need validation in human patient tumors. The specific role of KIF1Bβ as a tumor suppressor cooperating with NF1 in human disease needs clinical correlation. Summary based on abstract only.

Source: bioRxiv — 2026-04-10