Figure 2 from <i>In Vivo</i> Modeling of Patient Genetic Heterogeneity Identifies New Ways to Target Cholangiocarcinoma

Figure 2 from <i>In Vivo</i> Modeling of Patient Genetic Heterogeneity Identifies New Ways to Target Cholangiocarcinoma

<p><i>In vivo</i> CRISPR-Cas9 screening identifies transforming mutations that interact with mutant Ras. <b>A,</b> Schematic of this study in which high-content sequencing data are collated from patients with ICC and the mutational profile of these tumors rationalized t...

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Bibliografski detalji
Glavni autor: Nicholas T. Younger (14956251) (author)
Daljnji autori: Mollie L. Wilson (14956254) (author), Anabel Martinez Lyons (14956257) (author), Edward J. Jarman (9773166) (author), Alison M. Meynert (14956260) (author), Graeme R. Grimes (14160170) (author), Konstantinos Gournopanos (14956263) (author), Scott H. Waddell (14956266) (author), Peter A. Tennant (14956269) (author), David H. Wilson (14956272) (author), Rachel V. Guest (14956275) (author), Stephen J. Wigmore (14915943) (author), Juan Carlos Acosta (14956278) (author), Timothy J. Kendall (14956281) (author), Martin S. Taylor (14956284) (author), Duncan Sproul (13971883) (author), Pleasantine Mill (256953) (author), Luke Boulter (14956287) (author)
Izdano: 2025
Teme:
Cancer
Cancer Biology
Molecular and Cellular Biology
Therapeutic Research and Development
Methods and Technology
Cell Signaling
Computational Methods
Sequence analysis
Drug Targets
Gastrointestinal Cancers
Liver cancer
Gene Technologies
Comparative genomics
Oncogenes & Tumor Suppressors
Kras
Preclinical Models
Animal models of cancer
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Opis
Sažetak:<p><i>In vivo</i> CRISPR-Cas9 screening identifies transforming mutations that interact with mutant Ras. <b>A,</b> Schematic of this study in which high-content sequencing data are collated from patients with ICC and the mutational profile of these tumors rationalized to identify novel, high confidence drivers of ICC. These putative drivers are used as input for an <i>in vivo</i> SpCas9/CRISPR screen to identify novel functional processes that drive ICC growth. <b>B,</b> Macroscopic images of the livers following injection with either NRAS<sup>G12V</sup> or KRAS<sup>G12D</sup> alone (left) or in combination with ICC<sup>Lib</sup> (right; dotted line, tumor). Scale bar, 1 cm. <b>C,</b> Quantification of macroscopic tumors per mouse at 10 weeks in mice bearing Nras<sup>G12V</sup> -expressing tumors and 8 weeks in those with Kras<sup>G12D</sup>-driven cancer. Each circle represents a different animal. <b>D,</b> The number of samples containing Indels in a particular gene following whole exome sequencing. Top graph lists those mutations found in both NRAS<sup>G12V</sup> and KRAS<sup>G12D</sup> tumors, and bottom graphs denote those mutations that are found only in KRAS<sup>G12D</sup> - or NRAS<sup>G12V</sup> -expressing tumors. Sample frequency (%) denotes the proportion of tumors containing any given mutation, whereas (count) is absolute number. (<i>N</i> represents anatomically discreet tumors recovered from at least four individual animals, KRAS<sup>G12D</sup><i>N</i> = 14 and NRAS<sup>G12V</sup><i>N</i> = 10.) <b>E,</b> PCA showing how samples group based on their transcriptomic signature and gRNA-induced mutations associated with each tumor type.</p>

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