לוח שנה משולב

Modern Genetics is revealing virtually all the genetic and epigenetic alterations associated with human malignancies. Mining this information for Precision Medicine is predicated on weeding out ‘bystander’ mutation and identifying the ‘driver’ mutations responsible for tumor initiation, progression and metastasis, as only the latter have diagnostic and therapeutic value. Secondly, we have to elucidate how driver mutations alter the fundamental molecular pathways governing tissue growth and identify actionable nodes within a given cancer gene network that can be exploited therapeutically.
The massive quantity of data emerging from cancer genomics therefore demands a corresponding increase in the efficiency and throughput of in vivo models to comprehensively assess all putative cancer genes. We therefore developed a versatile functional genomics toolbox that enables us to generate and analyze thousands of somatic gene knock-out or overexpression clones within a single animal in a matter of weeks. Ultrasound-guided in utero injections allow us to selectively transduce fluorescently-labeled lentiviral CRISPR or ORF libraries into various organs of living mouse embryos. Subsequent mosaic analysis, next-generation sequencing and library barcode deconvolution enables us to identify genes that regulate proliferation, differentiation and survival. Of note, this analysis not only assess the gene function in an physiological and immune-competent microenvironment, but can also be combined with any mouse model and treatment schedule to faithfully model human malignancies.
Using this technique, we have completed several proof-of-concept screens and elucidated several novel tumor suppressor genes in Head&Neck. Currently, we are performing several multiplexed in vivo CRISPR screens to uncover context-specific cancer vulnerabilities, novel immune regulators and genes that confer resistance to chemo- or targeted therapies. In this seminar, I will highlight the utility of direct in vivo screening to integrate human cancer genomics and mouse modeling for rapid and systematic discovery of cancer driver mutations and novel cancer vulnerabilities.