The Experimental Pathology Service at the University of Lausanne discuss the projects they cover
The Experimental Pathology Service at the University of Lausanne cover a range of topics with focus on cancer cells and tumor growths. Further information can be found on the website.
Targeting cancer stem cells in ewing’s sarcoma
We have shown that cancer stem cells (CSC) in Ewing’s sarcoma are maintained by transient deregulation of microRNA (miRNA) maturation resulting from epigenetically-mediated repression of TARBP2, which controls maturation of a range of miRNAs. This observation provides an indication as to how CSC may emerge and maintain their phenotype and suggests that CSC are in a dynamic cellular state and can lose their pluripotency and tumor initiating capacity just as selected tumor cells that compose the tumor bulk may acquire CSC features.
The object now is to determine the mechanisms that regulate TARBP2 repression in CSC and to explore pharmacological approaches to enhance TARBP2 activity so as to restore miRNA expression and abrogate the CSC phenotype. Combining such an approach with conventional chemotherapy that targets the tumor bulk should provide a powerful therapeutic option that could potentially change the prognosis of this particularly aggressive pediatric malignancy.
A major effort consists of characterizing the epigenetic changes that distinguish CSCs from bulk tumor cells in Ewing sarcoma and determining how such changes confer not only stem cell properties onto Ewing s sarcoma cells but also the ability to invade adjacent tissues, metastasize and resist conventional therapy.
The biology of synovial sarcoma
Synovial sarcoma (SS) is a highly aggressive soft tissue malignancy that affects primarily children and young adults. A “signature” chromosomal translocation t(X;18)(p11;q11) generates a fusion gene that encodes the fusion protein SYT-SSX, which is responsible for the pathogenesis SS.
However, the mechanism of action of SYT-SSX remains to be elucidated. Working with primary human SS and SS models, we are exploring molecular interactions initiated by SYT-SSX that lead to cellular transformation and identifying mechanisms that render primary cells permissive for oncogenic SYT-SSX activity.
Mesenchymal stem cells and sarcomagenesis
Tumor cell heterogeneity is well established in solid tumors, and an increasing number are recognized to possess a hierarchical organization at the summit of which are poorly differentiated cells that retain a degree of pluripotency, self-renewal capacity and tumor initiating potential, which together have led to the term cancer stem cells (CSC).
Virtually nothing is known about tumor cell heterogeneity in sarcomas and we are currently examining a broad range of sarcomas for the existence of relevant subpopulations of malignant cells that play a role in driving tumor growth and progression.
We are particularly interested in identifying epigenetic changes that may underlie tumor cell heterogeneity in different sarcoma types and determining how transformation by different oncogenetic events in distinct cellular contexts determines the epigenetic signature of tumors.
Mesenchymal stem cells and their role in the modulation of tumor growth
Numerous classes of stromal cells modulate tumor growth.
Mesenchymal stem cells (MSCs) are increasingly recognized to enhance growth of divergent tumor types but the underlying mechanisms are unclear. We are assessing the effect of MSCs from different tissues and grown under different conditions on tumor growth and dissemination in vivo and are using a broad range of technologies to identify the mechanisms that underlie the observed effects.
A major effort is directed toward understanding MSC-mediated immune suppression as a means to facilitate tumor progression.
Regulation of cell motility, secretion and the the DNAdamage response by lipid sensors in tumor cells
Maintenance or enhancement of motility and secretion are essential properties of most malignant cells. We are addressing mechanisms that regulate microtubule dynamics whose altered activity may enhance tumor cell motility and invasiveness and facilitate shape change. Our investigations have led us to identify lipid sensors localized in the endoplasmic reticulum that control microtubule dynamics in cancer cells. The same lipid sensors play a role in regulating the DNA damage response (DDR) and controlling the cell cycle. We are addressing the mechanisms whereby lipid sensors regulate seemingly divergent cellular functions and dissecting signaling pathways that induce or repress lipid sensor-dependent microtubule function and DDR.
In parallel, we are studying mechanisms that enhance tumor cell exocytosis. Exocytosis may play an important role in the delivery of proteolytic enzymes and other molecules to the extracellular matrix, helping create a path for tumor cell migration. We are focusing on the exploration of novel pathways that implicate hydrolase transport from the Golgi directly to lysosomes and the extracellular space and on understanding how targeting these pathways may impair tumor invasion and metastasis.
RNA binding proteins in cancer stem cells
RNA binding proteins are implicated in a broad range of functions in normal and malignant cells.
We have shown recently that the IGF2mRNA binding protein Imp2 plays a major role in regulating cancer stem cell metabolism in glioblastoma. We are pursuing these studies further to understand the mechanisms whereby Imps may regulate normal and cancer stem cell biology, focusing in particular on their implication in degrading or, alternatively, stabilizing selected microRNAs in addition to regulating mRNA transport and metabolism.