Colorectal cancer is one of the most common and deadliest types of cancer in the Western world. Altered regulation of cell death pathways is generally believed to contribute to tumor development and to therapy resistance. Colorectal cancer is characterized by an enormous genetic heterogeneity. One of the few frequently mutated genes is the KRAS oncogene. Our research over the past years has focused on elucidating how this oncogene affects cell death pathways and how that contributes to metastasis formation and drug resistance.
We discovered that the presence of oncogenic KRAS promotes chemotherapy-induced apoptosis via the intrinsic apoptosis pathway and have provided mechanistic insight into this phenomenon (Smakman et al, Cancer Research 2006; de Bruijn et al, Br J Cancer, 2010; Raats et al, Cell Oncol, 2011). We are currently testing whether KRAS-induced ‘priming’ of CRC cells for apoptosis can be exploited therapeutically. This is done by rationally combining standard chemotherapy with novel therapeutics targeting apoptosis regulators.
While oncogenic KRAS promotes apoptosis induced via the intrinsic pathway, it protects cells from apoptosis induced by “death receptor ligands” like CD95L (FasL) and TRAIL. This is not simply due to activation of survival pathways, or to death receptor inactivation, but to a drastic change in their signaling output. In the presence of oncogenic KRAS, death receptors fail to induce apoptosis but become invasion-inducing receptors instead. We also elucidated the signal transduction pathway that is responsible for this phenomenon. This pathway plays a central role in the capacity of tumor cells to metastasize and regulates the growth behavior of micro-metastases in the liver (Hoogwater et al Gastroenterology, 2010; Nijkamp et al J Hepatol 2010; Steller et al, EMBO Reports, 2011). We are currently evaluating the importance of this novel metastasis pathway in a large series of patient-derived tumor cell cultures.
Colorectal tumors contain a subpopulation of ‘Cancer Stem Cells’ (CSC) that drive tumor growth, similar to normal stem cells that drive turnover of intestinal tissue. CSC-enriched colonopshere cultures can be established from resection specimens of primary colorectal tumors or metastases. We established a novel collection of such colonospheres (Emmink et al, Gastroenterology, 2011) as a platform for translational research. In particular, we are testing the contribution of CSC’s to chemotherapy resistance and to metastasis formation.