Neuroblastoma-associated chromosomal aberrations drive cell identity loss in human neural crest via disruption of developmental regulators DOI Creative Commons
Ingrid M. Saldana-Guerrero, Luis F. Montaño-Gutierrez, Katy Boswell

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2022, Volume and Issue: unknown

Published: Nov. 23, 2022

Abstract Early childhood tumours arise from transformed embryonic cells, which often carry large copy number alterations (CNA). However, it remains unclear how CNAs contribute to tumourigenesis due a lack of suitable models. Here we employ female human stem cell (hESC) differentiation and single-cell transcriptome epigenome analysis assess the effects chromosome 17q/1q gains, are prevalent in embryonal tumour neuroblastoma (NB). We show that impair specification trunk neural crest (NC) cells their sympathoadrenal derivatives, putative cells-of-origin NB. This effect is exacerbated upon overexpression MYCN , whose amplification co-occurs with Moreover, potentiate pro-tumourigenic mutant NC resemble NB tumours. These changes correlate stepwise aberration developmental transcription factor networks. Together, our results sketch mechanistic framework for CNA-driven initiation

Language: Английский

Efficacy and tolerability of neoadjuvant therapy with Talimogene laherparepvec in cutaneous basal cell carcinoma: a phase II trial (NeoBCC trial) DOI Creative Commons
Julia Maria Ressler, Maud Plaschka, Rita Silmbrod

et al.

Nature Cancer, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 16, 2025

We present a single-arm, phase II, neoadjuvant trial with the oncolytic virus talimogene laherparepvec (T-VEC) in 18 patients difficult-to-resect cutaneous basal cell carcinomas. The primary end point, defined as proportion of patients, who after six cycles T-VEC (13 weeks), become resectable without need for plastic reconstructive surgery, was already achieved stage I (9 patients; 50.0%); thus study discontinued early success. objective response rate 55.6% and complete pathological 33.3%. Secondary points included safety, relapse-free survival overall survival, time to occurrence new carcinomas biological read outs. Only mild adverse events occurred. 6-month rates were 100%. In two carcinoma diagnosed. led significant increase cytotoxic T cells (P = 0.0092), B 0.0004) myeloid 0.0042) decrease regulatory 0.0290) within tumor microenvironment. Together, represents viable treatment option (EudraCT no. 2018-002165-19).

Language: Английский

Citations

1
A human neural crest model reveals the developmental impact of neuroblastoma-associated chromosomal aberrations DOI Creative Commons
Ingrid M. Saldana-Guerrero, Luis F. Montaño-Gutierrez, Katy Boswell

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: May 3, 2024

Abstract Early childhood tumours arise from transformed embryonic cells, which often carry large copy number alterations (CNA). However, it remains unclear how CNAs contribute to tumourigenesis due a lack of suitable models. Here we employ female human stem cell (hESC) differentiation and single-cell transcriptome epigenome analysis assess the effects chromosome 17q/1q gains, are prevalent in embryonal tumour neuroblastoma (NB). We show that impair specification trunk neural crest (NC) cells their sympathoadrenal derivatives, putative cells-of-origin NB. This effect is exacerbated upon overexpression MYCN , whose amplification co-occurs with Moreover, potentiate pro-tumourigenic mutant NC resemble NB tumours. These changes correlate stepwise aberration developmental transcription factor networks. Together, our results sketch mechanistic framework for CNA-driven initiation

Language: Английский

Citations

7
Reprogramming of tumor-associated macrophages via NEDD4-mediated CSF1R degradation by targeting USP18 DOI Creative Commons

Sayuri Miyauchi,

Kei‐ichiro Arimoto,

Mengdan Liu

et al.

Cell Reports, Journal Year: 2023, Volume and Issue: 42(12), P. 113560 - 113560

Published: Dec. 1, 2023

Tumor-associated myeloid cells modulate the tumor microenvironment and affect progression. Type I interferon (IFN-I) has multiple effects on tumors immune response, ubiquitin-specific peptidase 18 (USP18) functions as a negative regulator of IFN-I signal transduction. This study aims to examine function in during Here, we show that deletion USP18 suppresses Enhanced signaling blocked expression prompt downregulation colony stimulating factor 1 receptor (CSF1R) polarization tumor-associated macrophages toward pro-inflammatory phenotypes. Further vitro experiments reveal CSF1R is mediated by ubiquitin-proteasome degradation via E3 ligase neural precursor cell-expressed, developmentaly downregulated 4 (NEDD4) IFN-induced increase ubiquitin E2 ubiquitin-conjugating enzyme H5. impairs ubiquitination subsequent interrupting NEDD4 binding CSF1R. These results previously unappreciated role macrophage regulating suggest targeting myeloid-lineage an effective strategy for IFN-based therapies.

Language: Английский

Citations

14
Building and analyzing metacells in single-cell genomics data DOI Creative Commons
Mariia Bilous, Léonard Hérault, Aurélie AG Gabriel

et al.

Molecular Systems Biology, Journal Year: 2024, Volume and Issue: 20(7), P. 744 - 766

Published: May 29, 2024

Language: Английский

Citations

4
IL-18R supported CAR T cells targeting oncofetal tenascin C for the immunotherapy of pediatric sarcoma and brain tumors DOI Creative Commons
Elizabeth Wickman, Shannon Lange, Jessica Wagner

et al.

Journal for ImmunoTherapy of Cancer, Journal Year: 2024, Volume and Issue: 12(11), P. e009743 - e009743

Published: Nov. 1, 2024

Background Oncofetal splice variants of extracellular matrix (ECM) proteins present a unique group target antigens for the immunotherapy pediatric cancers. However, limited data is available if these can be targeted with T cells expressing chimeric antigen receptors (CARs). Methods To determine expression oncofetal version tenascin C (TNC) encoding domain (C.TNC) in brain and solid tumors, we used quantitative reverse transcription PCR immunohistochemistry. Genetically modified were generated from human peripheral blood mononuclear evaluated vitro vivo. Results We demonstrate that C.TNC expressed on protein level including diffuse intrinsic pontine glioma, osteosarcoma, rhabdomyosarcoma, Ewing sarcoma. generate C.TNC-CAR establish recognize kill C.TNC-positive tumor cells. their antitumor activity vivo limited. improve effector function cells, design leucine zipper-based cytokine receptor activates interleukin-18 signaling pathways (Zip18R). Expression Zip18R improves ability to secrete cytokines expand repeat stimulation assays. C.TNC-CAR.Zip18R also have significantly greater compared unmodified Conclusions Our study identifies ECM TNC as promising CAR T-cell therapy tumors tumors. While focus here cancer, our work has relevance broad range adult cancers express C.TNC.

Language: Английский

Citations

4
BRAFV600E induces key features of LCH in iPSCs with cell type-specific phenotypes and drug responses DOI Creative Commons
Giulio Abagnale, Raphaela Schwentner, Philipp Ben Soussia-Weiss

et al.

Blood, Journal Year: 2024, Volume and Issue: 145(8), P. 850 - 865

Published: Dec. 4, 2024

Langerhans cell histiocytosis (LCH) is a clonal hematopoietic disorder defined by tumorous lesions containing CD1a+/CD207+ cells. Two severe complications of LCH are systemic hyperinflammation and progressive neurodegeneration. The scarcity primary samples lack appropriate models limit our mechanistic understanding pathogenesis affect patient care. We generated human in vitro model for using induced pluripotent stem cells (iPSCs) harboring the BRAFV600E mutation, most common genetic driver LCH. show that BRAFV600E/WT iPSCs display myelomonocytic skewing during hematopoiesis spontaneously differentiate into similar to lesional derived from CD14+ progenitor. modulates expression key transcription factors regulating monocytic differentiation leads an upregulation proinflammatory molecules marker genes early myeloid differentiation. In drug testing revealed BRAFV600E-induced transcriptomic changes reverted upon treatment with mitogen-activated protein kinase (MAPK) pathway inhibitors (MAPKis). Importantly, MAPKis do not progenitors but reduce only mature population. Furthermore, iPSC-derived neurons (iNeurons) cocultured microglia-like cells, differentiated CD34+ progenitors, exhibit signs neurodegeneration neuronal damage release neurofilament light chain. summary, iPSC-based described here provides platform investigate effects different types tool compare identify novel approaches BRAFV600E-driven diseases.

Language: Английский

Citations

3
Allometry of cell types in planarians by single cell transcriptomics DOI Creative Commons
Elena Emili, Alberto Pérez-Posada, Maria D. Christodoulou

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Nov. 4, 2023

Abstract Allometry explores the relationship between an organism’s body size and its various components, offering insights into ecology, physiology, metabolism, disease. The cell is basic unit of biological systems, yet, study type allometry remains relatively unexplored. Single-cell RNA sequencing (scRNA-seq) provides a promising tool for investigating allometry. Planarians, capable growing degrowing following allometric scaling rules, serve as excellent model such studies. We used scRNA-seq to examine in asexual planarians different sizes, revealing that they consist same types but varying proportions. Notably, gut basal cells are most responsive changes size, suggesting role energy storage. capture gene regulatory programs distinct response size. This research sheds light on molecular cellular aspects underscores utility investigations.

Language: Английский

Citations

9
Building and analyzing metacells in single-cell genomics data DOI Creative Commons
Mariia Bilous, Léonard Hérault, Aurélie AG Gabriel

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Feb. 8, 2024

Abstract The advent of high-throughput single-cell genomics technologies has fundamentally transformed biological sciences. Currently, millions cells from complex tissues can be phenotypically profiled across multiple modalities. scaling computational methods to analyze such data is a constant challenge and tools need regularly updated, if not redesigned, cope with ever-growing numbers cells. Over the last few years, metacells have been introduced reduce size complexity while preserving biologically relevant information. Here, we review recent studies that capitalize on concept – many variants in nomenclature used. We further outline how when should (or not) used study what considered analyzing at metacell level. To facilitate exploration metacells, provide comprehensive tutorial construction analysis RNA-seq ( https://github.com/GfellerLab/MetacellAnalysisTutorial ) as well fully integrated pipeline rapidly build, visualize evaluate different https://github.com/GfellerLab/MetacellAnalysisToolkit ).

Language: Английский

Citations

1
A PERTURBATION CELL ATLAS OF HUMAN INDUCED PLURIPOTENT STEM CELLS DOI Creative Commons
Sami Nourreddine,

Yesh Doctor,

Amir Dailamy

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 4, 2024

Towards comprehensively investigating the genotype-phenotype relationships governing human pluripotent stem cell state, we generated an expressed genome-scale CRISPRi Perturbation Cell Atlas in KOLF2.1J induced cells (hiPSCs) mapping transcriptional and fitness phenotypes associated with 11,739 targeted genes. Using phenotypes, created a minimum distortion embedding map of demonstrating rich recapitulation protein complexes, such as strong co-clustering MRPL, BAF, SAGA, Ragulator family members. Additionally, uncovered regulators that are uncoupled from fitness, discovering potential novel pluripotency (JOSD1, RNF7) metabolic factors (ZBTB41). We validated these findings via phenotypic, protein-interaction, tracing assays. Finally, propose contrastive human-cell engineering framework (CHEF), machine learning architecture learns perturbation atlases to predict recipes achieve desired states. Taken together, our study presents comprehensive resource for interrogating regulatory networks pluripotency.

Language: Английский

Citations

1
Eed controls craniofacial osteoblast differentiation and mesenchymal proliferation from the neural crest DOI Open Access

Tim Casey-Clyde,

Siyuan Liu, Juan A. Cámara

et al.

Published: Nov. 22, 2024

The histone methyltransferase Polycomb repressive complex 2 (PRC2) is required for specification of the neural crest, and mis-regulation crest development can cause severe congenital malformations. PRC2 necessary induction, but embryonic, cellular, molecular consequences activity after induction are incompletely understood. Here we show that Eed , a core subunit PRC2, craniofacial osteoblast differentiation mesenchymal proliferation crest. Integrating mouse genetics with single-cell RNA sequencing, our results reveal conditional knockout cell causes hypoplasia, impaired osteogenesis, attenuated first evident in post-migratory populations. We drives vivo primary cultures by regulating diverse transcription factor programs cells. These data enhance understanding epigenetic mechanisms underlie development, shed light on drivers rare syndromes humans.

Language: Английский

Citations

1