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Characterization of Intestinal Cancer Cell Invasion

Periodic Reporting for period 1 - CICCI (Characterization of Intestinal Cancer Cell Invasion)

Reporting period: 2015-04-01 to 2017-03-31

Colorectal cancer is the second leading cause of cancer related death in the Western world, with invasion of the primary tumour and eventually metastasis being the leading cause of mortality. Classic chemotherapy (e.g. 5-fluoruracil (5-FU)) in combination with angiogenesis blocking reagents (e.g. Bevacizumab) is used to slightly improve survival of patients with late stage colorectal cancer. Nevertheless, long-term survival cannot be achieved with either of these strategies, partly due to the recurrence of tumours from latent tumour cells. Therefore, it is essential that new therapeutic strategies for metastatic colorectal cancer are tested and developed.
To understand the process of invasion and metastasis formation in more detail, I generated protocols to identify integrin αvβ6 (ITGB6) positive invading colorectal cancer cells, a known specific marker for this cell type. Analysis of these cells I identified Notch1 signalling as being highly active in this particular cell population. I utilised genetic activation of this signalling pathway in intestinal epithelial cells to generate an autochthonous genetically engineered mouse model (GEMM) with low latency and high metastatic penetrance (100%). Since no highly metastatic colorectal cancer GEMMs have been generated previously, such a model is of high demand for pre-clinical late stage colorectal cancer research. Transcriptomic profiling and cross comparison with human datasets show that this mouse model recapitulates the molecular basis of the most aggressive form of human colorectal cancer that has dismal survival rates. I have also shown that cell lines derived from primary tumours and metastases, taken from this model, share characteristics of highly aggressive human colorectal cancer cell lines. Overall this model fills a massive gap in pre-clinical research of late stage colorectal cancer and will be beneficial for the entire research community and potentially the pharmaceutical industry. This model will help to identify new therapeutic strategies as well as improve the existing ones.
I also investigated the changes in stem cell populations during intestinal cancer progression. Intestinal stem cells have been described to be the cell-of-origin of intestinal tumours, but a clear gap in the knowledge of the function and contribution to tumour progression of cancer stem cells prompted me to investigate colorectal cancer stem cell number and characteristics in more detail. To investigate colorectal cancer stem cell populations, I utilized two intestinal cancer models resulting in either non-invasive adenoma or invasive adenocarcinoma, in combination with a recently developed random slippage allele. This lineage tracing approach gave for the first time the opportunity to assess the quantity of functional stem cells in adenoma versus adenocarcinoma, in a reporter independent manner. These analyses revealed that colorectal cancer stem cell numbers are not changed during disease progression and therefore indicate that targeting of colorectal cancer stem cells is a strategy to challenge late stage colorectal cancer.
The ground breaking, highly metastatic autochthonous genetically engineered mouse model, generated in this project, will help to gain massive new insights into the process of colorectal cancer metastasis and will help to improve therapies for patients suffering from late stage colorectal cancer. The model represents a strong new tool to investigate late stage colorectal cancer and I anticipate that this model will be used by pre-clinical researchers in academia and the pharmaceutical industry to improve existing and to discover new therapies.
Hematoxylin-Eosin stain of an intestinal primary tumour from the newly developed mouse model