Stepwise-edited, human melanoma models reveal mutations' effect on tumor and microenvironment.
Science
; 376(6592): eabi8175, 2022 04 29.
Article
em En
| MEDLINE
| ID: mdl-35482859
ABSTRACT
Establishing causal relationships between genetic alterations of human cancers and specific phenotypes of malignancy remains a challenge. We sequentially introduced mutations into healthy human melanocytes in up to five genes spanning six commonly disrupted melanoma pathways, forming nine genetically distinct cellular models of melanoma. We connected mutant melanocyte genotypes to malignant cell expression programs in vitro and in vivo, replicative immortality, malignancy, rapid tumor growth, pigmentation, metastasis, and histopathology. Mutations in malignant cells also affected tumor microenvironment composition and cell states. Our melanoma models shared genotype-associated expression programs with patient melanomas, and a deep learning model showed that these models partially recapitulated genotype-associated histopathological features as well. Thus, a progressive series of genome-edited human cancer models can causally connect genotypes carrying multiple mutations to phenotype.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Neoplasias Cutâneas
/
Melanoma
Limite:
Humans
Idioma:
En
Revista:
Science
Ano de publicação:
2022
Tipo de documento:
Article
País de afiliação:
Estados Unidos