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An In Vivo CRISPR Screen Identifies Stepwise Genetic Dependencies of Metastatic Progression
- Source :
- Cancer Res, Cancer Research, 82 (4)
- Publication Year :
- 2021
-
Abstract
- Blood-borne metastasis of breast cancer involves a series of tightly regulated sequential steps, including the growth of a primary tumor lesion, intravasation of circulating tumor cells (CTC), and adaptation in various distant metastatic sites. The genes orchestrating each of these steps are poorly understood in physiologically relevant contexts, owing to the rarity of experimental models that faithfully recapitulate the biology, growth kinetics, and tropism of human breast cancer. Here, we conducted an in vivo loss-of-function CRISPR screen in newly derived CTC xenografts, unique in their ability to spontaneously mirror the human disease, and identified specific genetic dependencies for each step of the metastatic process. Validation experiments revealed sensitivities to inhibitors that are already available, such as PLK1 inhibitors, to prevent CTC intravasation. Together, these findings present a new tool to reclassify driver genes involved in the spread of human cancer, providing insights into the biology of metastasis and paving the way to test targeted treatment approaches.<br />Cancer Research, 82 (4)<br />ISSN:0008-5472<br />ISSN:1538-7445
- Subjects :
- Mice, Knockout
Cancer Research
Breast Neoplasms
Cell Cycle Proteins
Mice, SCID
Protein Serine-Threonine Kinases
Neoplastic Cells, Circulating
Survival Analysis
Xenograft Model Antitumor Assays
Article
Gene Expression Regulation, Neoplastic
Oncology
Mice, Inbred NOD
Cell Line, Tumor
Proto-Oncogene Proteins
Biomarkers, Tumor
Animals
Humans
Clustered Regularly Interspaced Short Palindromic Repeats
Female
RNA-Seq
CRISPR-Cas Systems
Neoplasm Metastasis
RNA, Guide, Kinetoplastida
Subjects
Details
- ISSN :
- 15387445 and 00085472
- Volume :
- 82
- Issue :
- 4
- Database :
- OpenAIRE
- Journal :
- Cancer research
- Accession number :
- edsair.doi.dedup.....7c2ec7c048654d42190295b43ff19e36