In Vivo Modeling of Patient Genetic Heterogeneity Identifies New Ways to Target Cholangiocarcinoma

Intrahepatic cholangiocarcinoma (ICC) is an aggressive malignancy of the bile ducts within the liver characterized by high levels of genetic heterogeneity. In the context of such genetic variability, determining which oncogenic mutations drive ICC growth has been difficult, and developing modes of p...

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Published inCancer research (Chicago, Ill.) Vol. 82; no. 8; pp. 1548 - 1559
Main Authors Younger, Nicholas T, Wilson, Mollie L, Martinez Lyons, Anabel, Jarman, Edward J, Meynert, Alison M, Grimes, Graeme R, Gournopanos, Konstantinos, Waddell, Scott H, Tennant, Peter A, Wilson, David H, Guest, Rachel V, Wigmore, Stephen J, Acosta, Juan Carlos, Kendall, Timothy J, Taylor, Martin S, Sproul, Duncan, Mill, Pleasantine, Boulter, Luke
Format Journal Article
LanguageEnglish
Published United States American Association for Cancer Research 15.04.2022
Subjects
Bile Duct Neoplasms - genetics
Bile Duct Neoplasms - pathology
Bile Ducts, Intrahepatic - pathology
Cholangiocarcinoma - genetics
Cholangiocarcinoma - pathology
Genetic Heterogeneity
Humans
Molecular Cell Biology
Phosphatidylinositol 3-Kinases - genetics
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Abstract Intrahepatic cholangiocarcinoma (ICC) is an aggressive malignancy of the bile ducts within the liver characterized by high levels of genetic heterogeneity. In the context of such genetic variability, determining which oncogenic mutations drive ICC growth has been difficult, and developing modes of patient stratification and targeted therapies remains challenging. Here we model the interactions between rare mutations with more common driver genes and combine in silico analysis of patient data with highly multiplexed in vivo CRISPR-spCas9 screens to perform a functional in vivo study into the role genetic heterogeneity plays in driving ICC. Novel tumor suppressors were uncovered, which, when lost, cooperate with the RAS oncoprotein to drive ICC growth. Focusing on a set of driver mutations that interact with KRAS to initiate aggressive, sarcomatoid-type ICC revealed that tumor growth relies on Wnt and PI3K signaling. Pharmacologic coinhibition of Wnt and PI3K in vivo impeded ICC growth regardless of mutational profile. Therefore, Wnt and PI3K activity should be considered as a signature by which patients can be stratified for treatment independent of tumor genotype, and inhibitors of these pathways should be levied to treat ICC. This work shows that, despite significant genetic heterogeneity, intrahepatic cholangiocarcinoma relies on a limited number of signaling pathways to grow, suggesting common therapeutic vulnerabilities across patients.
AbstractList This work shows that, despite significant genetic heterogeneity, intrahepatic cholangiocarcinoma relies on a limited number of signaling pathways to grow, suggesting common therapeutic vulnerabilities across patients. Intrahepatic cholangiocarcinoma (ICC) is an aggressive malignancy of the bile ducts within the liver characterized by high levels of genetic heterogeneity. In the context of such genetic variability, determining which oncogenic mutations drive ICC growth has been difficult, and developing modes of patient stratification and targeted therapies remains challenging. Here we model the interactions between rare mutations with more common driver genes and combine in silico analysis of patient data with highly multiplexed in vivo CRISPR-spCas9 screens to perform a functional in vivo study into the role genetic heterogeneity plays in driving ICC. Novel tumor suppressors were uncovered, which, when lost, cooperate with the RAS oncoprotein to drive ICC growth. Focusing on a set of driver mutations that interact with KRAS to initiate aggressive, sarcomatoid-type ICC revealed that tumor growth relies on Wnt and PI3K signaling. Pharmacologic coinhibition of Wnt and PI3K in vivo impeded ICC growth regardless of mutational profile. Therefore, Wnt and PI3K activity should be considered as a signature by which patients can be stratified for treatment independent of tumor genotype, and inhibitors of these pathways should be levied to treat ICC.
Intrahepatic cholangiocarcinoma (ICC) is an aggressive malignancy of the bile ducts within the liver characterized by high levels of genetic heterogeneity. In the context of such genetic variability, determining which oncogenic mutations drive ICC growth has been difficult, and developing modes of patient stratification and targeted therapies remains challenging. Here we model the interactions between rare mutations with more common driver genes and combine in silico analysis of patient data with highly multiplexed in vivo CRISPR-spCas9 screens to perform a functional in vivo study into the role genetic heterogeneity plays in driving ICC. Novel tumor suppressors were uncovered, which, when lost, cooperate with the RAS oncoprotein to drive ICC growth. Focusing on a set of driver mutations that interact with KRAS to initiate aggressive, sarcomatoid-type ICC revealed that tumor growth relies on Wnt and PI3K signaling. Pharmacologic coinhibition of Wnt and PI3K in vivo impeded ICC growth regardless of mutational profile. Therefore, Wnt and PI3K activity should be considered as a signature by which patients can be stratified for treatment independent of tumor genotype, and inhibitors of these pathways should be levied to treat ICC. This work shows that, despite significant genetic heterogeneity, intrahepatic cholangiocarcinoma relies on a limited number of signaling pathways to grow, suggesting common therapeutic vulnerabilities across patients.
Intrahepatic cholangiocarcinoma (ICC) is an aggressive malignancy of the bile ducts within the liver characterized by high levels of genetic heterogeneity. In the context of such genetic variability, determining which oncogenic mutations drive ICC growth has been difficult, and developing modes of patient stratification and targeted therapies remains challenging. Here we model the interactions between rare mutations with more common driver genes and combine in silico analysis of patient data with highly multiplexed in vivo CRISPR-spCas9 screens to perform a functional in vivo study into the role genetic heterogeneity plays in driving ICC. Novel tumor suppressors were uncovered, which, when lost, cooperate with the RAS oncoprotein to drive ICC growth. Focusing on a set of driver mutations that interact with KRAS to initiate aggressive, sarcomatoid-type ICC revealed that tumor growth relies on Wnt and PI3K signaling. Pharmacologic coinhibition of Wnt and PI3K in vivo impeded ICC growth regardless of mutational profile. Therefore, Wnt and PI3K activity should be considered as a signature by which patients can be stratified for treatment independent of tumor genotype, and inhibitors of these pathways should be levied to treat ICC.Intrahepatic cholangiocarcinoma (ICC) is an aggressive malignancy of the bile ducts within the liver characterized by high levels of genetic heterogeneity. In the context of such genetic variability, determining which oncogenic mutations drive ICC growth has been difficult, and developing modes of patient stratification and targeted therapies remains challenging. Here we model the interactions between rare mutations with more common driver genes and combine in silico analysis of patient data with highly multiplexed in vivo CRISPR-spCas9 screens to perform a functional in vivo study into the role genetic heterogeneity plays in driving ICC. Novel tumor suppressors were uncovered, which, when lost, cooperate with the RAS oncoprotein to drive ICC growth. Focusing on a set of driver mutations that interact with KRAS to initiate aggressive, sarcomatoid-type ICC revealed that tumor growth relies on Wnt and PI3K signaling. Pharmacologic coinhibition of Wnt and PI3K in vivo impeded ICC growth regardless of mutational profile. Therefore, Wnt and PI3K activity should be considered as a signature by which patients can be stratified for treatment independent of tumor genotype, and inhibitors of these pathways should be levied to treat ICC.This work shows that, despite significant genetic heterogeneity, intrahepatic cholangiocarcinoma relies on a limited number of signaling pathways to grow, suggesting common therapeutic vulnerabilities across patients.SIGNIFICANCEThis work shows that, despite significant genetic heterogeneity, intrahepatic cholangiocarcinoma relies on a limited number of signaling pathways to grow, suggesting common therapeutic vulnerabilities across patients.
Author Sproul, Duncan
Jarman, Edward J
Wilson, Mollie L
Grimes, Graeme R
Guest, Rachel V
Mill, Pleasantine
Gournopanos, Konstantinos
Tennant, Peter A
Meynert, Alison M
Wilson, David H
Kendall, Timothy J
Martinez Lyons, Anabel
Acosta, Juan Carlos
Younger, Nicholas T
Wigmore, Stephen J
Waddell, Scott H
Taylor, Martin S
Boulter, Luke
AuthorAffiliation 2 Clinical Surgery, University of Edinburgh, Royal Infirmary of Edinburgh, Edinburgh, United Kingdom
4 Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom
3 Cancer Research UK Edinburgh Centre, Institute of Genetics and Cancer, Crewe Road South, Edinburgh, United Kingdom
1 MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, United Kingdom
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Current address for N.T. Younger and D.H. Wilson: Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom.
N.T. Younger and M.L. Wilson contributed equally to this article.
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Snippet Intrahepatic cholangiocarcinoma (ICC) is an aggressive malignancy of the bile ducts within the liver characterized by high levels of genetic heterogeneity. In...
This work shows that, despite significant genetic heterogeneity, intrahepatic cholangiocarcinoma relies on a limited number of signaling pathways to grow,...
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SubjectTerms Bile Duct Neoplasms - genetics
Bile Duct Neoplasms - pathology
Bile Ducts, Intrahepatic - pathology
Cholangiocarcinoma - genetics
Cholangiocarcinoma - pathology
Genetic Heterogeneity
Humans
Molecular Cell Biology
Phosphatidylinositol 3-Kinases - genetics
Title In Vivo Modeling of Patient Genetic Heterogeneity Identifies New Ways to Target Cholangiocarcinoma
URI https://www.ncbi.nlm.nih.gov/pubmed/35074757
https://www.proquest.com/docview/2622657471
https://pubmed.ncbi.nlm.nih.gov/PMC9359731
Volume 82
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