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Clonal dynamics and tumor cell heterogeneity in colorectal cancer
Clonal dynamics and tumor cell heterogeneity in colorectal cancer
Colon cancers are composed of phenotypically heterogeneous tumor cell subpopulations with variable expression of putative stem cell and differentiation antigens. While in normal colonic mucosa clonal repopulation occurs among differentiation gradients from crypt base towards crypt apex, the clonal architecture of colon cancer and the relevance of tumor cell subpopulations for clonal outgrowth are poorly understood. In the first study of this thesis, we used a multicolor lineage tracing approach in colon cancer xenografts that reflect primary colon cancer architecture. With this method, we could demonstrate that clonal outgrowth is mainly driven by tumor cells located at the leading tumor edge with clonal axis formation towards the tumor center. Our findings suggest that in colon cancer tumor cell position may be more important for clonal outgrowth than tumor cell phenotype. In a second study we analyzed colon cancer cells with high WNT signaling activity. This characteristic overactivation in colorectal cancers is caused by pathway activating mutations and drives tumor progression and metastasis. Here, we could identify pre-leukemia transcription factor 3 (PBX3) as a gene regulated in part by WNT signaling in colon cancers and assess its prognostic value. In a colon cancer case collection, PBX3 expression correlated with nuclear β-catenin and high PBX3 levels were associated with decreased patient survival and an increased risk for tumor relapse and metastasis. Additionally, an independent case control study confirmed the association of high PBX3 expression and colon cancer metastasis to the liver. Further studies provide evidence that PBX3 is also regulated by EMT. Knockdown and overexpression studies modifying the EMT transcriptions factors SNAIL and ZEB1 as well as PBX3 demonstrated that PBX3 is part of an EMT-regulatory network in colorectal cancer. Taken together the results of these two studies may have implications for the cancer stem cell hypothesis, reveal new aspects of tumor cell heterogeneity in colorectal cancer, and could furthermore give insights for the design of new therapeutic strategies.
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Lamprecht, Sebastian
2018
English
Universitätsbibliothek der Ludwig-Maximilians-Universität München
Lamprecht, Sebastian (2018): Clonal dynamics and tumor cell heterogeneity in colorectal cancer. Dissertation, LMU München: Faculty of Medicine
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Abstract

Colon cancers are composed of phenotypically heterogeneous tumor cell subpopulations with variable expression of putative stem cell and differentiation antigens. While in normal colonic mucosa clonal repopulation occurs among differentiation gradients from crypt base towards crypt apex, the clonal architecture of colon cancer and the relevance of tumor cell subpopulations for clonal outgrowth are poorly understood. In the first study of this thesis, we used a multicolor lineage tracing approach in colon cancer xenografts that reflect primary colon cancer architecture. With this method, we could demonstrate that clonal outgrowth is mainly driven by tumor cells located at the leading tumor edge with clonal axis formation towards the tumor center. Our findings suggest that in colon cancer tumor cell position may be more important for clonal outgrowth than tumor cell phenotype. In a second study we analyzed colon cancer cells with high WNT signaling activity. This characteristic overactivation in colorectal cancers is caused by pathway activating mutations and drives tumor progression and metastasis. Here, we could identify pre-leukemia transcription factor 3 (PBX3) as a gene regulated in part by WNT signaling in colon cancers and assess its prognostic value. In a colon cancer case collection, PBX3 expression correlated with nuclear β-catenin and high PBX3 levels were associated with decreased patient survival and an increased risk for tumor relapse and metastasis. Additionally, an independent case control study confirmed the association of high PBX3 expression and colon cancer metastasis to the liver. Further studies provide evidence that PBX3 is also regulated by EMT. Knockdown and overexpression studies modifying the EMT transcriptions factors SNAIL and ZEB1 as well as PBX3 demonstrated that PBX3 is part of an EMT-regulatory network in colorectal cancer. Taken together the results of these two studies may have implications for the cancer stem cell hypothesis, reveal new aspects of tumor cell heterogeneity in colorectal cancer, and could furthermore give insights for the design of new therapeutic strategies.