Genetic drivers of metastatic colorectal cancer liver colonization

Kajba, Christina Marie

dc.contributor.advisor	Dobbelstein, Matthias Prof. Dr.
dc.contributor.author	Kajba, Christina Marie
dc.date.accessioned	2025-02-20T18:07:08Z
dc.date.available	2025-04-17T00:50:11Z
dc.date.issued	2025-02-20
dc.identifier.uri	http://resolver.sub.uni-goettingen.de/purl?ediss-11858/15839
dc.identifier.uri	http://dx.doi.org/10.53846/goediss-11091
dc.format.extent	56	de
dc.language.iso	eng	de
dc.rights.uri	http://creativecommons.org/licenses/by/4.0/
dc.subject.ddc	610	de
dc.title	Genetic drivers of metastatic colorectal cancer liver colonization	de
dc.type	doctoralThesis	de
dc.contributor.referee	Dobbelstein, Matthias Prof. Dr.
dc.date.examination	2025-03-19	de
dc.description.abstracteng	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.	de
dc.contributor.coReferee	Krause, Petra PD Dr.
dc.subject.eng	colorectal cancer	de
dc.subject.eng	metastasis	de
dc.subject.eng	liver colonization	de
dc.subject.eng	ITPR3	de
dc.identifier.urn	urn:nbn:de:gbv:7-ediss-15839-5
dc.affiliation.institute	Medizinische Fakultät	de
dc.subject.gokfull	Medizin (PPN619874732)	de
dc.description.embargoed	2025-04-16	de
dc.identifier.ppn	1917851669
dc.identifier.orcid	0000-0002-7896-0744	de
dc.notes.confirmationsent	Confirmation sent 2025-02-20T19:45:01	de

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