Genetic drivers of metastatic colorectal cancer liver colonization

by Christina Marie Kajba
Doctoral thesis
Date of Examination:2025-03-19
Date of issue:2025-02-20
Advisor:Prof. Dr. Matthias Dobbelstein
Referee:Prof. Dr. Matthias Dobbelstein
Referee:PD Dr. Petra Krause
Persistent Address: http://dx.doi.org/10.53846/goediss-11091

 

 

Files in this item

Name:KajbaC_thesis_SUB.pdf
Size:2.11Mb
Format:PDF
Description:Dissertation

This file will be freely accessible after 2025-04-16.

Abstract

English

Metastasis is the leading cause of death from colorectal cancer (CRC), yet the genes and pathways driving CRC metastatic progression are poorly defined. Among the steps in the metastatic cascade, liver colonization is a key bottleneck and a promising target for clinical intervention. Using xenograft and syngeneic mouse models, we validated three hits from a previous genome-wide liver colonization screen as causal drivers of CRC metastasis in vivo: ITPR3, an intracellular calcium channel; RELB, a transcription factor in the non-canonical NFkb pathway; and UBR4, an E3 ubiquitin-protein ligase. We subsequently focused on ITPR3 for further characterization and mechanistic follow-up. Analysis of publicly available transcriptomic data revealed increased ITPR3 expression in human liver metastases and modulation of upstream pathways toward enhanced ITPR3 signaling. Furthermore, genes within these pathways differentially regulated liver metastatic progression in vivo. Functional experiments showed that ITPR3 deficiency reduces early metastatic cancer cell survival in vivo and hinders CRC cell proliferation and colony formation under conditions of cellular detachment in vitro. Collectively, these findings suggest that ITPR3 promotes colorectal cancer metastasis by enabling CRC cells to survive transient substratum detachment during early liver colonization.
Keywords: colorectal cancer; metastasis; liver colonization; ITPR3