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CRISPR-Barcoding for Intratumor Genetic Heterogeneity Modeling and Functional Analysis of Oncogenic Driver Mutations

Abstract : Intratumor genetic heterogeneity underlies the abilityof tumors to evolve and adapt to different environmental conditions. Using CRISPR/Cas9 technologyand specific DNA barcodes, we devised a strategyto recapitulate and trace the emergence of subpopulations of cancer cells containing a mutation ofinterest. We used this approach to model differentmechanisms of lung cancer cell resistance to EGFRinhibitors and to assess effects of combined drugtherapies. By overcoming intrinsic limitations of current approaches, CRISPR-barcoding also enablesinvestigation of most types of genetic modifications,including repair of oncogenic driver mutations.Finally, we used highly complex barcodes insertedat a specific genome location as a means of simultaneously tracing the fates of many thousands ofgenetically labeled cancer cells. CRISPR-barcodingis a straightforward and highly flexible method thatshould greatly facilitate the functional investigation ofspecific mutations, in a context that closely mimicsthe complexity of cancer.
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https://hal-normandie-univ.archives-ouvertes.fr/hal-02376161
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Submitted on : Friday, November 22, 2019 - 1:45:59 PM
Last modification on : Tuesday, June 30, 2020 - 3:32:45 AM

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Alexis Guernet, Sathish kumar Mungamuri, Dorthe Cartier, Ravi Sachidanandam, Anitha Jayaprakash, et al.. CRISPR-Barcoding for Intratumor Genetic Heterogeneity Modeling and Functional Analysis of Oncogenic Driver Mutations. Molecular Cell, Elsevier, 2016, 63 (3), pp.526-538. ⟨10.1016/j.molcel.2016.06.017⟩. ⟨hal-02376161⟩

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