Biology subjects

Adameyko, I. I.

Publications and source records attributed to Adameyko, I. I..

4 recordsLinked to original sources

bioRxiv2026

Sympathoadrenal Lineage Plasticity Drives Intratumoral Heterogeneity in Paraganglioma, Neuroblastoma and Composite Tumors Following KIF1Bb-NF1 Loss

Neuroblastoma (NB) and paraganglioma (PPGL) arise from the sympathoadrenal lineage, yet their developmental relationship and heterogeneity remain unclear. Single-cell and spatial transcriptomics revealed shared, spatially organized developmental states, including populations characteristic of the other tumor type, chromaffin-like cells in NB and neuroblast-like cells in PPGL and hybrids co-expressing adjacent states. Deconvolution of an independent PPGL cohort associated metastatic disease most strongly with chromaffin hybrid states, alongside connecting progenitor-like, cycling neuroblast, and early chromaffin identities, whereas non-metastatic tumors were enriched for differentiated late chromaffin identities. In mice, combined loss of the candidate 1p36 tumor suppressor KIF1B{beta} and NF1 recapitulates these developmental architectures by prolonging developmental plasticity, reactivating embryonic neurogenic programs, and driving chromaffin-to-neuroblast transitions generating pheochromocytoma, neuroblastoma and composite tumors. Mouse tumors contained discrete spatial domains of developmental and neoplastic states that mirrored those in human PPGL. Together, our findings establish chromaffin-neuroblast plasticity as a mechanism of sympathoadrenal tumor heterogeneity and identify hybrid developmental states as a potential indicator of plasticity associated with metastatic PPGL.

cancer biology↗

bioRxiv2024

Unbiased profiling of multipotency landscapes reveals spatial modulators of clonal fate biases

The proportion of cell types varies systematically across the body, but it remains unclear how individual progenitor cells integrate positional information to establish patterns of cellular composition. In this study we profile the clonal landscape of the embryo, using single-cell lineage tracing of mouse embryos from neurulation until mid-gestation. To analyze the complex clonal patterns derived from highly multipotent progenitors, we developed clone2vec, which uses unsupervised learning to categorize individual clones into lineages based on shared transcriptional context. This revealed a body-wide gradient of clonal fate biases, in which anatomical position and clonal composition are mutually predictive. Comparison of clonal lineages revealed spatial transcription factor programs associated with dynamic cell biasing towards skeletal versus non-skeletal fates. Mosaic combinatorial perturbations targeting the Hedgehog pathway generated clones in which positional identity was mismatched with clonal composition, suggesting a potential signaling influence on somite patterning. We explore the effects of position and heterochrony on fate biases in cranial, trunk, and caudal neural crest clones. Altogether, our work demonstrates an effective practical approach for dissecting mechanisms of lineage specification.

developmental biology↗

bioRxiv2023

SOX2+ sustentacular cells are stem cells of the postnatal adrenal medulla

Renewal of the catecholamine-secreting chromaffin cell population of the adrenal medulla is necessary for physiological homeostasis throughout life. Definitive evidence for the presence or absence of an adrenomedullary stem cell has been enigmatic. In this work, we demonstrate that a subset of sustentacular cells endowed with a support role, are in fact adrenomedullary stem cells. Through genetic tracing and comprehensive transcriptomic data of the mouse adrenal medulla, we show that cells expressing Sox2/SOX2 specialise as a unique postnatal population from embryonic Schwann Cell Precursors and are also present in the normal adult human adrenal medulla. Postnatal SOX2+ cells give rise to chromaffin cells of both the adrenaline and noradrenaline lineages in vivo and in vitro. We reveal that SOX2+ stem cells have a second, paracrine role in maintaining adrenal chromaffin cell homeostasis, where they promote proliferation through paracrine secretion of WNT6. This work identifies SOX2+ cells as a true stem cell for catecholamine-secreting chromaffin cells.

developmental biology↗

bioRxiv2023

Motor nerves direct the development of the sympathetic nervous system

The sympathetic nervous system controls a wide spectrum of bodily functions including operation of vessels, cardiac rhythm, and the "flight or fight response". Sympathetic neurons, which are neural crest-derived, develop in coordination with presynaptic motor nerves extending from the central nervous system (CNS). By using nerve-selective genetic ablations, we revealed that sympathetic ganglia development depends on CNS-derived motor innervation. In the absence of preganglionic motor nerves, trunk sympathetic chain ganglia were fragmented and smaller in size, while cervical ganglia were severely misshapen. Sympathetic neurons were misplaced along sensory fibers and projected towards abnormal paths, in some cases invading the sensory dorsal root ganglia. The misplaced progenitors of sympathoblasts corresponded to the nerve-associated, neural crest-derived Schwann cell precursors (SCPs). Notably, we found that SCPs activate the autonomic marker PHOX2B while migrating along motor nerves towards the region of the dorsal aorta in wildtype embryos, suggesting that SCP differentiate into sympathetic neurons while still nerve-associated in motor-ablated embryos. Ligand-receptor prediction from single cell transcriptomic data coupled with functional studies identified Semaphorin 3A/3F as candidate motor nerve-derived signals influencing neural crest migration along axons. Thus, motor nerves control the placement of sympathoblasts and their subsequent axonal navigation during critical periods of sympathetic chain development.

developmental biology↗