The aim is to analyze the role of cancer-associated alterations of cell surface glycosylation on malignancy and metastasis progression. Metastatic tumor cells “communicate” with the cells in their microenvironment, which consist predominantly of inflammatory cells. An important component of altered tumor cell behavior is the presence of microbiota, particularly in colorectal cancer. We study the significance of cell-cell communication between tumor cells and inflammatory cells within the tumor microenvironment during tumorigenesis and tissue-specific metastasis.
Tumor cell glycosylation promotes metastasis
Altered glycosylation correlated with cancer progression and poor prognosis due to metastasis particularly in epithelial cancers (carcinomas). Enhanced expression of carcinoma-associated glycan structures carrying selectin ligands correlate with metastatic progression. One of a common glycan epitopes found on carcinomas is the terminal tetrasaccharide sialyl Lewisx and sialyl Lewisa, which consistently correlates with tumor progression, metastatic spread, and poor prognosis. Blood borne metastasis is caused by spread of tumor cells through circulation. The selectins are well-characterized vascular receptors for certain sLex/a-containing, mucin-type glycoproteins, suggesting their implication in the process of metastasis. We study the involvement of selectins in leukocyte recruitment and promotion of metastasis.
Metastasis is not a random process, and rather follows the metastatic traits of tumor cells which are expressed in their capacity to adopt the new environment (tissue) for the growth of a tumor. While there is accumulating evidence that the composition of a metastatic microenvironment is an important part of successful metastasis, the exact molecular mechanisms remains to be defined. Using several spontaneously metastatic mouse models we aim to define the stromal components of specific organs involved in tissue specific metastasis of different cancers (e.g. breast, lung colon).
Cell signaling and cancer
Cancer progression is linked with altered expression of factors that act as autocrine activators or induce changes in cytokines of the microenvironment essential for metastatic colonization. Deregulation of transcription factors is linked to malignant transformation, affecting cell differentiation, proliferation, adhesion and metastasis. In addition, tumors avoid the immune system through modulation of the recruitment, expansion and function of tumor-infiltrating leukocytes. Tumor cells deficient in certain transcription factors and specific inhibitors of cytokine pathways (chemokines and growth factors) are being used to determine their function in formation of a tumor microenvironment and metastasis using a variety of mouse models.
Gut microbiota and colorectal cancer progression
Changes in gut microbiota are associated with several diseases, including intestinal inflammation, metabolic syndromes and cancer. Mucins are the major carrier of glycans in intestinal lumen, supporting both microbiota niche formation and homeostasis. The observed dysbiosis in colorectal cancer patients was associated with enhanced colonization with mucin-degrading bacteria, however; the molecular mechanism how they contribute to cancer progression remains unclear. We study how changes in gut microbiota affect tumor progression, with a focus on the role of leukocytes.
- Confocal fluorescent microscopy, and live imaging
- Advanced flow cytometry and cell sorting
- CRISPR/cas9 mediated gene disruption in cell lines and animal models
- Genomics and transcriptomics using next generation sequencing
- Cancer mouse models (transgenic and knock-out mice) for orthotopic tumors and spontaneous metastasis
- Glycan analysis
- Analysis of heparin derivatives as potential inhibitors of metastasis