Biology subjects

Schlisio, S.

Publications and source records attributed to Schlisio, S..

5 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

HIF2α negatively regulates MYCN protein levels and promotes a low-risk noradrenergic phenotype in neuroblastoma.

The role of HIF2, encoded by EPAS1, in neuroblastoma remains controversial. Here we demonstrate that induction of high levels of HIF2 in MYCN-amplified neuroblastoma cells results in a rapid and profound reduction of the oncoprotein MYCN. This is followed by an upregulation of genes characteristic of noradrenergic cells in the adrenal medulla. Additionally, upon induction of HIF2, the proliferation rate drops substantially, and cells develop elongated neurite-like protrusions, indicative of differentiation. In vivo HIF2 induction in established xenografts significantly attenuates tumour growth. Notably, analysis of sequenced neuroblastoma patient samples, revealed a negative correlation between EPAS1 and MYCN expression and a strong positive correlation between EPAS1 expression, high expression levels of noradrenergic markers, and improved patient outcome. This was paralleled by analysis of human adrenal medulla datasets wherein EPAS1 expression was prominent in populations with high expression levels of genes characteristic of noradrenergic chromaffin cells. Our findings show that high levels of HIF2 in neuroblastoma, leads to drastically reduced MYCN protein levels, cell cycle exit, and noradrenergic cell differentiation. Taken together, our results challenge the dogma that HIF2 acts as an oncogene in neuroblastoma and rather suggest that HIF2 has potential tumour suppressor capacity in this particular disease. Significance statementHIF2 has been proposed as a neuroblastoma oncogene and a tractable target for clinical intervention, this has been questioned by several studies. Thus, it is necessary to move beyond correlative studies and better determine the function of HIF2 in neuroblastoma. Our study shows that induced expression of HIF2 in MYCN-amplified neuroblastoma substantially reduces MYCN protein levels and attenuates proliferation while it induces several features of noradrenergic differentiation and impedes xenograft tumour growth. Together with bioinformatic analysis of sequenced neuroblastoma patient samples and the developing human adrenal medulla, this couples HIF2 to low-risk neuroblastoma with a substantially better patient outcome. Thus, in neuroblastoma HIF2 exhibit tumour suppressor capacity rather than oncogenic capacity.

cancer biology↗

bioRxiv2024

A genetically engineered therapeutic lectin inhibits human influenza A virus infection and sustains robust virus-specific CD8 T cell expansion

Native banana lectin (BanLec) is antiviral but highly mitogenic, which limits its therapeutic value. In contrast, the genetically engineered H84T BanLec (H84T) is not mitogenic but remains effective against influenza A virus (IAV) infection in mouse models. However, the potency and effect of H84T on human immune cells and IAV-specific immune responses is undetermined. We found that H84T efficiently inhibited IAV replication in human dendritic cells (DCs) from blood and tonsils, which preserved DC viability and allowed acquisition and presentation of viral antigen. Consequently, H84T-treated DCs initiated effective expansion of IAV-specific CD8 T cells. Furthermore, H84T preserved the capacity of IAV-exposed DCs to present a second non-IAV antigen and induce robust CD8 T cell expansion. This supports H84T as a potent antiviral in humans as it effectively inhibits IAV infection without disrupting DC function, and preserves induction of antigen-specific adaptive immune responses against diverse antigens, which likely is clinically beneficial.

immunology↗

bioRxiv2021

Single-nuclei transcriptomes from human adrenal gland reveals distinct cellular identities of low and high-risk neuroblastoma tumors.

Childhood neuroblastoma has a remarkable variability in outcome. Age at diagnosis is one of the most important prognostic factors, with children less than 1 year old having favorable outcomes. We studied single-cell and single-nuclei transcriptomes of neuroblastoma with different clinical risk groups and stages, including healthy adrenal gland. We compared tumor cell populations with embryonic mouse sympatho-adrenal derivatives, and post-natal human adrenal gland. We provide evidence that low and high-risk neuroblastoma have different cell identities, representing two disease entities. Low-risk neuroblastoma presents a transcriptome that resembles sympatho- and chromaffin cells, whereas malignant cells enriched in high-risk neuroblastoma resembles an unknown subtype of TRKB+ cholinergic progenitor population identified in human post-natal gland. Analyses of these populations revealed different gene expression programs for worst and better survival in correlation with age at diagnosis. Our findings reveal two cellular identities and a composition of human neuroblastoma tumors reflecting clinical heterogeneity and outcome.

cancer biology↗

bioRxiv2019

Splicing-sensitive fusion transcripts associated with key tumor characteristics occur at high frequency in neuroblastoma

The paucity of recurrent mutations has hampered efforts to understand and treat neuroblastoma. Alternative splicing and splicing-dependent RNA-fusions represent mechanisms able to increase the gene product repertoire but their role in neuroblastoma remains largely unexplored. Through analysis of RNA-sequenced neuroblastoma we here show that elevated expression of splicing factors is a strong predictor of poor clinical outcome. Furthermore, we identified >900 primarily intrachromosomal fusions containing canonical splicing sites. Fusions included transcripts from well-known oncogenes, were enriched for proximal genes and in chromosomal regions commonly gained or lost in neuroblastoma. As a proof-of-principle that these fusions can generate altered gene products, we characterized a ZNF451-BAG2 fusion, generating a truncated BAG2-protein which inhibited retinoic acid-induced differentiation. Spliceosome inhibition impeded neuroblastoma fusion expression, induced apoptosis and inhibited xenograft tumor growth. Our findings elucidate a splicing-dependent mechanism producing altered gene products in neuroblastoma and suggest that the spliceosome is a tractable therapeutical target.

cancer biology↗