Notch signaling maintains a progenitor-like subclass of hepatocellular carcinoma

Seidel, K.; Piscol, R.; Nguyen, T. T. T.; Shelton, A.; Cottonham, C.; de la Cruz, C. C.; Castillo, J.; Garcia, J.; Segal, E.; Merchant, M.; Yang, Y. A.; Chen, J.; Ahmed, M.; Scherl, A.; Vij, R.; Mosteiro, L.; Wu, Y.; Modrusan, Z.; Metcalfe, C.; Siebel, C. W.

doi:10.1101/2024.12.13.628320

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bioRxiv · 10.1101/2024.12.13.628320

Notch signaling maintains a progenitor-like subclass of hepatocellular carcinoma

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Abstract

Hepatocellular carcinomas (HCCs) constitute one of the few cancer indications for which mortality rates continue to rise. While Notch signaling dictates a key progenitor lineage choice during development, its role in HCC has remained controversial. Using therapeutic antibodies targeting Notch ligands and receptors to screen over 40 patient-derived xenograft models, we here identify progenitor-like HCCs that crucially depend on a tumor-intrinsic JAG1-NOTCH2 signal. Inhibiting this signal induces tumor regressions by triggering progenitor-to-hepatocyte differentiation, the same cell fate-switch that Notch controls during development. Transcriptomic analysis places the responsive tumors within the well-characterized progenitor subclass, a poor prognostic group of highly proliferative tumors, providing a diagnostic method to enrich for Notch-dependent HCCs. Furthermore, single-cell RNA sequencing uncovers a heterogeneous population of tumor cells and reveals how Notch inhibition shifts cells from a mixed cholangiocyte-hepatocyte lineage to one resembling mature hepatocytes. Analyzing the underlying transcriptional programs brings molecular detail to this process by showing that Notch inhibition de-represses expression of CEBPA, which enables the activity of HNF4, a hepatocyte lineage factor that is otherwise quiescent. We thus describe a compelling and targetable dependency in a poor-prognosis class of HCCs.

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Seidel, K., Piscol, R., Nguyen, T. T. T., Shelton, A., Cottonham, C., de la Cruz, C. C., Castillo, J., Garcia, J., Segal, E., Merchant, M., Yang, Y. A., Chen, J., Ahmed, M., Scherl, A., Vij, R., Mosteiro, L., Wu, Y., Modrusan, Z., Metcalfe, C., Siebel, C. W.. 2024-12-17. Notch signaling maintains a progenitor-like subclass of hepatocellular carcinoma. https://doi.org/10.1101/2024.12.13.628320

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