Researchers suggest that Wnt and PI3K signaling may add value to treatment stratification for patients with intrahepatic cholangiocarcinoma (iCCA) and the coinhibition of these pathways may constitute a relevant therapeutic approach, as published in Cancer Research.

The authors developed an in vivo, highly multiplexed CRISPR-SpCas9 (ie, using Streptococcus pyogenes Cas9) screening approach to identify tumor suppressors involved in Ras-induced senescence and tumor initiation. Among the set of genes identified, neurofibromin-2 (Nf2) emerged as a potential contributor to Ras-driven iCCA.

“In fact, of the 14 cancers from our screen that we exome sequenced, four of the five containing Nf2-mutations segregated away from the main cluster, suggesting that the addition of a mutation in Nf2 can functionally cooperate with KrasG12D and Trp53 mutations and affects the phenotype of iCCA,” the authors explained.

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The loss of Nf2 led to the formation of aggressive and poorly differentiated sarcomatoid-type iCCA, which was shown to be associated with deregulation of Wnt and PI3K signaling.

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“Our data demonstrates the importance of understanding the function of rare mutations in [iCCA] and shows that these low-frequency mutations not only influence the outcome of more common driver mutations, but also can lead us to define applicable therapeutic strategies that can be used to develop personalised approaches,” the authors said.

“Which could be applied clinically to stratify patients and treat [iCCA] of divergent genotypes based on the signalling pathways that are deregulated in these cancers.”

To enhance the biological meaning of the study, the authors first generated a high-confidence list of candidate driver genes using genomic data from patient datasets of cholangiocarcinoma.

This list was then used to screen against either KrasG12D or NrasG12V oncogenes in the CRISPR-SpCas9 system. Similar to other studies, this approach also showed that Kras mutations occur more frequently in iCCA than those in Nras.


Younger NT, Wilson ML, Martinez Lyons A, et al. In vivo modeling of patient genetic heterogeneity identifies new ways to target cholangiocarcinoma. Cancer Res. Published online January 24, 2022. doi:10.1158/0008-5472.CAN-21-2556