Single-cell RNA sequencing reveals intratumoral heterogeneity in primary uveal melanomas and identifies HES6 as a driver of the metastatic disease.
Journal
Cell death and differentiation
ISSN: 1476-5403
Titre abrégé: Cell Death Differ
Pays: England
ID NLM: 9437445
Informations de publication
Date de publication:
06 2021
06 2021
Historique:
received:
04
08
2020
accepted:
29
12
2020
revised:
27
12
2020
pubmed:
20
1
2021
medline:
24
2
2022
entrez:
19
1
2021
Statut:
ppublish
Résumé
Intratumor heterogeneity has been recognized in numerous cancers as a major source of metastatic dissemination. In uveal melanomas, the existence and identity of specific subpopulations, their biological function and their contribution to metastasis remain unknown. Here, in multiscale analyses using single-cell RNA sequencing of six different primary uveal melanomas, we uncover an intratumoral heterogeneity at the genomic and transcriptomic level. We identify distinct transcriptional cell states and diverse tumor-associated populations in a subset of the samples. We also decipher a gene regulatory network underlying an invasive and poor prognosis state driven in part by the transcription factor HES6. HES6 heterogenous expression has been validated by RNAscope assays within primary human uveal melanomas, which further unveils the existence of these cells conveying a dismal prognosis in tumors diagnosed with a favorable outcome using bulk analyses. Depletion of HES6 impairs proliferation, migration and metastatic dissemination in vitro and in vivo using the chick chorioallantoic membrane assay, demonstrating the essential role of HES6 in uveal melanomas. Thus, single-cell analysis offers an unprecedented view of primary uveal melanoma heterogeneity, identifies bona fide biomarkers for metastatic cells in the primary tumor, and reveals targetable modules driving growth and metastasis formation. Significantly, our findings demonstrate that HES6 is a valid target to stop uveal melanoma progression.
Identifiants
pubmed: 33462406
doi: 10.1038/s41418-020-00730-7
pii: 10.1038/s41418-020-00730-7
pmc: PMC8185008
doi:
Substances chimiques
Basic Helix-Loop-Helix Transcription Factors
0
HES6 protein, human
0
Repressor Proteins
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1990-2000Subventions
Organisme : Institut National Du Cancer (French National Cancer Institute)
ID : INCA-12824
Organisme : Agence Nationale de la Recherche (French National Research Agency)
ID : ANR-10-INBS-09-03
Organisme : Agence Nationale de la Recherche (French National Research Agency)
ID : ANR-10-INBS-09-02
Organisme : Agence Nationale de la Recherche (French National Research Agency)
ID : ANR-15-IDEX-01
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