Cancer . EMT . Drug Resistance . Gene Expression . Metastasis . Signal Transduction
Molecular dissection of malignant tumor progression,metastasis and therapy resistance
The vast majority of cancer patient deaths are due to the systemic dissemination of cancer cells throughout the body and the seeding and outgrowth of secondary tumors (metastases) in distant organs. One major objective of our research is the identification and characterization of those cancer cells that are able to initiate and complete the metastatic process and to overcome current cancer therapies.In particular, we focus on the molecular mechanisms underlying the transition from benign tumors to malignant cancers and the metastatic dissemination of tumor cells. Moreover, we have set out to delineate the genes and pathways that allow cancer cells to evade from therapy. In addition to cultured tumor cell lines in vitro, we employ transplantation and transgenic mouse models of specific cancer types to determine causal connections between the expression of particular genes and tumor progression, metastasis and drug resistance in vivo.
The development of malignant tumors is in part characterized by a tumor cell's capability to overcome cell-cell adhesion and to invade surrounding tissue by a process referred to as epithelial-mesenchymal-transition (EMT). An EMT underlies the conversion of epithelial, differentiated cells to mesenchymal, migratory and invasive cells. In the past years, we have learned that an EMT occurs in multiple stages and is regulated by sophisticated molecular networks regulating the expression of a large number of protein, lncRNA and miRNA-encoding genes. More recently, we have noted that an EMT also selects for cancer cells exhibiting hallmarks of cancer stem cells and increased drug resistance. Notably, we have identified a large number of transcription factors that act as master regulators not only in the initiation and execution of the morphogenic process of an EMT but also in providing survival signals to cancer cells and thus allowing cancer cells to seed and grow metastases in distant organs. We investigate the direct target genes of these transcription factors and their role in tumor metastasis. We also assess the role of miRNAs and lnRNAs and their target genes in the regulation of an EMT and of metastatic dissemination.With these experimental approaches we aim at identifying the master regulators of an EMT and cancer metastasis and we plan to scrutinize their potential as therapeutic targets for preventing metastatic disease.
In a second line of research, we investigate the molecular pathways underlying the development of evasive resistance to targeted cancer therapy. We employ a number of cultured cancer cell lines and mouse models to study the pathological, physiological and molecular consequences of therapies targeting tumor angiogenesis and malignant tumor progression. In particular, we use cell biological,biochemical and bioinformatical analysis to delineate the molecular pathways allowing cancer cells to escape from targeted therapy. Recently, we have found that tumors shift their metabolism to glycolysis and acquire a status of metabolic symbiosis between individual cells of a tumor to overcome anti-angiogenic therapy. Finally, in collaboration with pharmaceutical companies we are investigating the efficacy and biological consequences of various anti-angiogenic and anti-metastatic cancer treatments.
Fig. 1: Tead2 upregulation and Yap/Taz subcellular localization during EMT. Morphological differences between epithelial and mesenchymal counterparts of murine breast cancer cells (phase contrast, scale bar, 50 μm). Immunofluorescent staining of Tead2 and its co-factors Yap and Taz shows their increased expression and nuclear translocation in mesenchymal cells where they activate the expression of genes involved in EMT and metastasis. E-cadherin staining shows epithelial cell junctions. DAPI was used to visualize nuclei (scale bars, 25 μm; Diepenbruck, Waldmeier et al., 2014).
Fig. 2: IGF-II production as a public goods games network. The microscopic picture shows a co-culture of cancer cells which do not produce IGF-II (colorless cells) and cancer cells which express IGF-II (green cells). Both cell types require IGF-II for their survival and they compete against each other to reach a specific homeostasis of producer cells and consumer cells. Guess who will win (answer: Archetti et al., 2015).
Fig. 3: Targeting metabolic symbiosis overcomes resistance to anti-angiogenic therapy. Metabolic symbiosis as a mechanism underlying evasive resistance to anti-angiogenic therapy by the multi-kinase inhibitors nintedanib and sunitinib. Inhibition of glycolysis by 3PO or genetic ablation of the lactate exporter MCT4 in tumor cells disrupts metabolic symbiosis, overrides therapy resistance, and suppresses tumor growth (Pisarsky, Bill et al., 2016).