Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Matak, A.
Characterization of cancer specific mechanisms in hepatobiliary carcinoma
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] Graz Medical University; 2019. pp. 161
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- Autor*innen der Med Uni Graz:
- Betreuer*innen:
- Kostner Gerhard
- Speicher Michael
- Zatloukal Kurt
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- Abstract:
- Intratumor heterogeneity is increasingly recognized as a major factor affecting diagnosis and personalized treatment of cancer. Even in genetically homogeneous cell populations, there is a substantial amount of phenotypic diversity of cancer cells, including specific cells that sustain cancers. Non-genetic heterogeneity of cells is often associated with the acquisition of malignant properties, such as cancer stem-like states, drug resistance, and metastatic properties, and such tumor cells can transition between different states irreversibly or reversibly. In this work, I identified stochastic phenotype switching as a novel aspect of non-genetic dynamics contributing to tumor heterogeneity in sarcomatoid cholangiocarcinoma. Analysis of single cell-derived clonal populations of primary tumor cell cultures using the lineage marker keratin-7 identified different types of self-propagating clones characterized by either stable or unstable expression of the lineage marker. Clonal cells are either keratin-7 positive or keratin-7 negative (stable phenotypes), or constantly changing the expression of the lineage marker (unstable phenotype). These phenotypes persisted in subsequent single cell-derived populations. Whole-genome methylation analysis revealed differential methylation of the keratin-7 promoter regulating its expression levels. Transcriptome sequencing showed that switching between keratin-7 phenotypes was linked to changes in the expression of several genes, some of which were related to the epithelial-mesenchymal transition. In xenotransplantation assays, keratin-7 negative phenotype showed increased tumorigenic potential, which correlates with the keratin-7 negative phenotype of the metastases of the primary tumor of these cells. Changes in multiple signaling pathways that mutually coordinate and cooperate are required for complex biological processes in cancer, like cell growth and formation of metastases. The well-known RAS oncogene alone is not a sufficient driver for tumorigenesis but needs cooperating factors. There is a need to identify novel pathways and genes that are involved in cancer growth and metastasis in Ras-driven cancers. Here I show that Cathepsin F (CTSF), a cystatin-like cysteine protease with a well-established role in physiological and pathological processes is also a novel tumor suppressor gene in hepatocellular carcinoma. I have shown that CTSF is significantly downregulated in hepatocellular carcinoma compared to non-neoplastic liver tissues. CTSF negatively correlates with increased tumor grade and proliferation marker Ki-67, and p53. Patients with resected CTSF-negative HCC had significantly poorer 10-year overall survival compared to CTSF-positive HCC. Reduced CTSF expression in HCC is a potential marker of HCC progression, invasiveness, and poor survival. Collectively, I studied two relevant features in hepatobiliary carcinoma using two different approaches. First, I describe non-genetic heterogeneity in sarcomatoid cholangiocarcinoma giving another twist to the current conceptual picture of intratumor heterogeneity. Second, I validated a new prognosis marker in hepatocellular cancer, which implies clinical relevance by segregating hepatocellular patients into categories of good and poor prognosis patients. This body of work significantly advances the understanding of important cancer-specific mechanisms involved in hepatobiliary carcinoma.