Cell state dynamics and plasticity in tumorigenesis

Acquired cancer therapy resistance is the direct consequence of pre-existing intratumor heterogeneity.

Intratumor heterogeneity is a hallmark of high-risk pediatric neuroblastoma (NB) which underpins dismal prognosis and treatment outcomes.

Apart from a well-recognized “genetic mosaicism”, when tumors are comprised of several clones with distinct mutations, neuroblastomas have recently been shown to exhibit striking phenotypic drift upon treatment and changes in local microenvironment.

Denoted as “tumor plasticity”, the latter phenomenon does not appear to stem from de novo genetic mutations but is rather driven by complex transcriptional rearrangements in neuroblastoma cells triggered by still poorly understood signaling clues.

Phenotypic plasticity thus comprises a new dimension of intratumor heterogeneity, mechanisms of which need to be properly understood to develop more efficient treatments.

Here we introduce a analytic approach based on space-resolved single nuclei transcriptomics with integrated mass spectrometry on human neuroblastoma and paraganglioma.

Our work is supplemented by mechanistic studies in animal neuroblastoma and paraganglioma models, enabling comparative differentiation trajectory analysis and lineage tracing of tumor subpopulations.

Collectively, the gained insights should expose the nature of intratumor heterogeneity and phenotypic plasticity in neuroblastoma and paraganglioma, improving prognostication and treatment options for this lethal cancer.