Due to copyright issues, an electronic copy of the thesis must be ordered from the faculty. For the faculty to have time to process the order, the order must be received by the faculty at the latest 2 days before the public defence. Orders received later than 2 days before the defence will not be processed. After the public defence, please address any inquiries regarding the thesis to the candidate.
Trial Lecture – time and place
See Trial Lecture.
Adjudication committee
- First opponent: Reader Philip Dunne, Queen's University Belfast, Northern Ireland
- Second opponent: Professor Kjetil Søreide, University of Bergen
- Third member and chair of the evaluation committee: Professor Kirsten Muri Boberg, University of Oslo
Chair of the Defence
Associate Professor Sheraz Yaqub, University of Oslo
Principal Supervisor
Associate Professor Anita Sveen, University of Oslo
Summary
Few patients with colorectal cancer benefit from precision medicine. Precision medicine is mainly used to treat metastatic cancers, but our knowledge of molecular tumor biology is predominantly derived from the primary tumor.
The aim of this thesis was to determine the extent and impact of metastatic tumor heterogeneity, by investigating molecular subtypes and model treatment responses in metastatic lesions. Gene expression profiles were compared among liver metastases and primary tumors from more than 800 patients. Personal tumor organoid models were generated from a patient who developed resistance to standard chemotherapy.
We developed a computational tool (CMScaller) to adapt the four consensus molecular subtypes (CMS1-4) of primary colorectal cancers to liver metastases. This confirmed a prognostic value of CMS among patients with metastatic disease. However, heterogeneity was pronounced, with frequent subtype-switching between primary tumors and metastases, and among metastatic lesions in each patient. We concluded that metastatic heterogeneity challenges the clinical utility of CMS, and developed a new classification directly from the gene expression profiles of metastases. The five liver metastasis subtypes (LMS1-5) appeared to originate from different progenitor cell types in the colon. LMS1 tumors had several features of aggressive biology and were associated with a poor patient outcome, independently of clinicopathological factors and tumor heterogeneity.
Drug sensitivity testing of tumor organoids from a patient with recurrent liver metastases could predict tumor response and resistance to chemotherapy. The drug LCL161 was identified as a potential experimental treatment after development of chemoresistance, by triggering the induction of apoptosis.
In summary, this thesis shows that detailed molecular and pharmacological models of metastatic tumor heterogeneity can provide a basis to predict patient prognosis and treatment response in colorectal cancer.
Additional information
Contact the research support staff.