A5045950452- CRISPR and Genetic Engineering
- CAR-T cell therapy research
- Mitochondrial Function and Pathology
- PI3K/AKT/mTOR signaling in cancer
- Colorectal Cancer Treatments and Studies
- Cancer Treatment and Pharmacology
- Genetic factors in colorectal cancer
- Cancer Immunotherapy and Biomarkers
- Immune Cell Function and Interaction
- Cancer Genomics and Diagnostics
- T-cell and B-cell Immunology
Oncode Institute
2022-2024
The Netherlands Cancer Institute
2022-2024
Whitehead Institute for Biomedical Research
2021
Howard Hughes Medical Institute
2020-2021
Massachusetts Institute of Technology
2020-2021
Broad Institute
2021
Significance The mTORC1 eukaryotic cell growth regulator dynamically responds to changes in environmental nutrient levels. While many upstream regulators are known modulate activity, the full complement of these is unknown. Here, using a genome-wide FACS-based CRISPR-Cas9 screen, we identify almost all positive as well others. results our screens highlighted importance mitochondrial health regulation mTORC1, which led us investigate how stress impinges on signaling. Ultimately, found that...
Abstract Genomics has greatly improved how patients with cancer are being treated; however, clinical-grade genomic biomarkers for chemotherapies currently lacking. Using whole-genome analysis of 37 metastatic colorectal (mCRC) treated the chemotherapy trifluridine/tipiracil (FTD/TPI), we identified KRAS codon G12 ( ) mutations as a potential biomarker resistance. Next, collected real-world data 960 mCRC receiving FTD/TPI and validated that were significantly associated poor survival, also in...
Tumor escape mechanisms for immunotherapy include deficiencies in antigen presentation, diminishing adaptive CD8+ T cell antitumor activity. Although innate natural killer (NK) cells are triggered by loss of MHC class I, their response is often inadequate. To increase tumor susceptibility to both and immune elimination, we performed parallel genome-wide CRISPR-Cas9 knockout screens under NK pressure. We identify all components, RNF31, RBCK1, SHARPIN, the linear ubiquitination chain assembly...
Genes limiting T cell antitumor activity may serve as therapeutic targets. It has not been systematically studied whether there are regulators that uniquely or broadly contribute to fitness. We perform genome-scale CRISPR-Cas9 knockout screens in primary CD8 cells uncover genes negatively impacting fitness upon three modes of stimulation: (1) intense, triggering activation-induced death (AICD); (2) acute, expansion; (3) chronic, causing dysfunction. Besides established regulators, we...
Abstract In mammalian cells, nutrients and growth factors signal through an array of upstream proteins to regulate the mTORC1 control pathway. Because full complement these has not been systematically identified, we developed a FACS-based CRISPR-Cas9 genetic screening strategy pinpoint genes that activity. Along with almost all known positive components pathway, identified many new impact activity, including DCAF7, CSNK2B, SRSF2, IRS4, CCDC43 , HSD17B10 . Using genome-wide data, generated...
3593 Background: Genomics-based precision medicine has greatly improved how patients with cancer are being treated targeted agents, but clinical-grade genomic biomarkers for chemotherapies currently lacking. The chemotherapeutic trifluridine/tipiracil (FTD/TPI) is approved the treatment of late-stage metastatic colorectal (mCRC). We aimed to find improve patient selection FTD/TPI in mCRC. Methods: In a discovery cohort FTD/TPI-treated mCRC (n = 37), genome-wide somatic variants were tested...