Chromaffin Cells with Sympathoblast Signature: Too Similar to Keep Apart?

Dong et al., 2020Dong R. Yang Zhan Y. Lai H.D. Ye C.J. Yao X.Y. Luo W.Q. Cheng X.M. Miao J.J. Wang J.F. al.Single-cell characterization of malignant phenotypes and developmental trajectories adrenal neuroblastoma.Cancer Cell. 2020; 38: 716-733Abstract Full Text PDF PubMed Scopus (49) Google Scholar built an atlas developing neural crest cells their derivatives in humans used it to trace the origins neuroblastoma. We compared these datasets with murine anlagen found that clusters designated as human chromaffin resemble sympathoblast mouse. Understanding development neural-crest-derived anlagen, events impairing its normal progression, could ultimately reveal sympathoadrenal malignancies including To address this question, we other researchers have developed vitro vivo models facilitated a hypothesis-driven interrogation various mechanisms distort neural-crest development. These studies are commonly conducted under assumption is possible recreate leading malignancy (particularly rodents). While morphological hormonal differences been noticed between mouse cortex, few described for medulla (e.g., cells; Aragao-Santiago 2017Aragao-Santiago L. Gomez-Sanchez C.E. Mulatero P. Spyroglou A. Reincke M. Williams T.A. Mouse primary aldosteronism: from physiology pathophysiology.Endocrinology. 2017; 158: 4129-4138Crossref (14) Scholar). The single-cell high-throughput techniques has eased faith during In particular, Furlan 2017Furlan Dyachuk V. Kastriti M.E. Calvo-Enrique Abdo H. Hadjab S. Chontorotzea T. Akkuratova N. Usoskin D. Kamenev al.Multipotent peripheral glial generate neuroendocrine medulla.Science. 357: eaal3753Crossref (146) characterized E12 E13 mice. authors identified sympathoblast, Schwann cell precursors (SCPs), chromaffin, SCP-chromaffin transitioning bridge cells) further analyzed expression signatures each clusters. recent paper, al. (Dong Scholar) similar approach humans. They obtained 2 whole early embryos [~4 post-conceptional weeks (PCW)], 4 fetal glands (8–14 PCW), 16 neuroblastoma tumors. calculated transcriptional similarities 9 meta-programs signature genes types (in both embryo), concluding several profile resembling sympathoblasts or (strongly prevalently) cells. Further, tested hypothesis heterogeneity occurs due proliferation differentiation. By defining gene undifferentiated (UCHC) differentiated (DCHCs), they state was most likely associated malignancy. study pointed out discrepancies previous (Boeva 2017Boeva Louis-Brennetot C. Peltier Durand Pierre-Eugène Raynal Etchevers H.C. Thomas Lermine Daudigeos-Dubus E. al.Heterogeneity identity defined by circuitries.Nat. Genet. 49: 1408-1413Crossref (169) Scholar; van Groningen 2017van Koster J. Valentijn L.J. Zwijnenburg D.A. Akogul Hasselt N.E. Broekmans Haneveld F. Nowakowska Bras al.Neuroblastoma composed two super-enhancer-associated differentiation states.Nat. 1261-1266Crossref (176) Scholar), proposed experiments using track fate NCC-related types. look understand extent which results be replicated mice (1) significantly higher (one-tail Welch’s test multiple correction Benjamini-Hochberg) (2) significant upregulation pairwise comparisons also Dong’s published deferentially expressed states gland (Table S4 selecting adjusted p < 0.01), embryo NCCs atlas, Table S6 al.), (3) 10 UCHC DCHC clusters, S8 al.). similarity estimated number 1:1 ortholog cluster shared significance Fisher’s exact corrected tests) score Scanpy average set – random genes, so represents non-random similarity; Wolf 2018Wolf F.A. Angerer Theis F.J. SCANPY: large-scale data analysis.Genome Biol. 2018; 19: 15Crossref (1154) Notably, consistently actually whereas large (Figure S1). Signature upregulated included epinephrine storage transport CHGA SLC18A1 Proenkephalin-encoding PENK. (excluding cycling lineages) STMN4, HAND1, ISL1. Importantly, PNMT among product catalyzes conversion norepinephrine epinephrine, property reason striking discrepancy needs clarified. cannot formally excluded inter-species differences, confused annotation Scholar, misled main conclusions obscured role Thus, suggest re-analyze ensure no such errors provide basis conclusions. computations handling project were performed on resources provided Swedish National Infrastructure Computing (SNIC) at sllstore2017016 , sens2018122 SNIC 2019/35-3 2019/3-462 2020/5-457 2020/6-171 2020/6-172 partially funded Research Council through grant agreements 2016-07213 2018-05973 . thank Johan Holmberg Monika Plescher insightful comments letter. Peter Kharchenko Igor Adameyko facilitating data. Funding: S.S. Childhood Cancer Fund Society Knut Alice Wallenberg Foundation ParaDiff supported ERC Synergy (KILL-OR-DIFFERENTIAT). Download .pdf (2.18 MB) Help pdf files Document S1. Figure S1 Response Kildsiute Bedoya-Reina SchlisioYang al.Cancer CellDecember 31, 2020In BriefWe appreciate Schlisio attention our work publication 2020). believe letters response will interest communities well many bioinformaticians. Full-Text Open ArchiveSingle-Cell Characterization Malignant Phenotypes Developmental Trajectories Adrenal NeuroblastomaDong CellSeptember 17, BriefDong detailed phenotypic landscape (NB) RNA sequencing show proliferation/differentiation status highly clinical NB. ArchivePitfalls Applying Markers Human Medullary CellsKildisiute BriefIn letter, generated demonstrate pitfalls relying marker annotate unbiased label transfer methods imply not cells, had suggested. ArchiveEvolutionary switch key markers leads mis-assignment medullaKameneva CellApril 29, 2021In would like clarify aspects ongoing discussion (Bedoya-Reina Schlisio, 2021; Kildisiute 2021b; 2021) regarding 2020), transcriptomics analysis medulla, followed comparison heterogeneous populations. grateful publishing valuable data, communal interpretation context pathological tissues. Archive