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Scientists have identified thousands of cancer gene mutations over the past 20 years, but understanding how these genetic mutations affect tumor growth and spread in the body remains a challenge because each patient's tumor may have many different genes mutation
This has led to the inference of genotype and phenotype linkages in cancer patients, and being able to systematically link genetic mutations or combinations of mutations in cancer with their phenotypes will greatly advance our understanding of cancer pathogenesis and help develop corresponding Treatment and medication
29 April 2022, Aviv Regev et al
The research team used CRISPR-Cas9 gene editing technology to sequentially edit five melanoma-related gene mutations or a combination in healthy human skin melanocytes
These edited cells grew and proliferated into tumors with melanoma characteristics, including rapid growth, enhanced invasiveness, and specific patterns of gene activation and pigmentation
Because the study can introduce one mutation at a time, the specific effects of specific genetic mutations and combinations of mutations can be determined
The study's lead author, Eran Hodis, is a doctoral student in the lab of Aviv Regev, now at Harvard's Brigham and Women's Hospital.
According to Eran Hodis, the study is the first to use precisely controlled genetic engineering techniques to create a human cancer model from fully differentiated cells rather than stem cells
This approach will provide the opportunity to create similar models in many other cancers, helping to accelerate the study of the association of cancer genetics with specific disease characteristics
To design these cancer models, precise gene editing techniques must be combined with high-resolution, massively parallel single-cell genomics analysis to generate and characterize cells and tumors, and to analyze the data through machine learning
Taken together, these findings give us an unprecedented understanding of which genetic mutations and combinations cause cells to become cancerous
When studying melanoma, linking its genotype to a specific trait or phenotype is especially difficult
Therefore, there are many genetic mutations in melanoma patients that are caused by external factors, and most of these genetic mutations are not drivers of melanoma
By introducing the gene mutation into healthy human melanocytes, the effect of the gene mutation on melanoma can be observed without interference
The research team first used CRISPR-Cas9 gene editing to sequentially introduce mutations in the genes CDKN2A, BRAF and TERT, which are normally found in melanomas in healthy human melanocytes
Next, the research team knocked out the known melanoma-related tumor suppressor genes PTEN, TP53, and APC in the above-mentioned cells to generate a total of nine different cell models:
• Wild-type human melanocytes (WT),
• CDKN2A-/- cells (C),
• CDKN2A-/-+BRAF V600E cells (CB),
• CDKN2A-/-+BRAF V600E+TERT-124C>T cells (CBT),
•CDKN2A-/-+BRAF V600E+TERT-124C>T+TP53-/- cells (CBT3),
•CDKN2A-/-+BRAF V600E+TERT-124C>T+PTEN-/- cells (CBTP),
• CDKN2A-/-+BRAF V600E+TERT-124C>T+APC-/- cells (CBTA),
•CDKN2A-/-+BRAF V600E+TERT-124C>T+PTEN-/-+TP53-/- cells (CBTP3),
•CDKN2A-/-+BRAF V600E+TERT-124C>T+PTEN-/-+APC-/- cells (CBTPA)
The research team implanted the above nine cell models into mice and observed them
.
Single-cell RNA sequencing revealed that these cells gradually altered their gene expression programs as more genetic mutations were introduced, and that mouse tumor models had similar gene expression patterns and pigmentation patterns to human melanoma patients with the same genotype
.
This suggests that the de novo melanoma cells faithfully mirror tumors in human melanoma patients
.
A striking feature of melanoma is the onset of metastasis at an early stage of the cancer, and this study clearly shows that CBTA cells and CBTPA cells are the most metastatic cells, that is, APC knockout cells are the most metastatic cells type, suggesting that inactivation of our APC gene may contribute to melanoma metastasis
.
The study also showed that CDKN2A-/-+BRAF V600E+TERT-124C>T mutations, when together, caused cells to behave like cancer cells and divide indefinitely
.
Tumors grew fastest when the above three mutations were combined with inactivation of the PTEN and TP53 genes
.
Overall, this study used CRISPR-Cas9 gene editing technology to edit human healthy melanocytes, gradually introducing 1 to 5 gene mutations, involving 6 gene mutations commonly found in melanoma, namely CDKN2A, BRAF, TERT, PTEN, TP53 , APC
.
A total of 9 cell models with different genes were constructed
.
These models were then characterized in vitro and in vivo using physiological assessments, histopathology, single-cell RNA sequencing, and machine learning algorithms
.
Through these cellular models, melanocyte genotypes correlate with phenotypes such as gene expression programs, replication and immortality, malignancy, rapid growth, pigmentation patterns, tumor metastasis, and histopathological features
.
and identified genetic mutations responsible for melanoma growth, metastasis and changes in the tumor microenvironment
.
In addition, this study not only revealed key genetic mutations in melanoma, but also provided a new way to study the role of specific genes in cancer
.