Investigation of the role of microtubule dynamics in paracrine signaling and cell invasion in human cancer cells

Abstract

Metastasis is a critical characteristic of aggressive human cancer, which is determined by the acquirement of increased cancer cell migration and invasion capabilities. Recent published work indicated that supernumerary centrosomes, which are frequently seen in cancer cells, induce a paracrine signaling contributing to enhanced cell invasion in breast epithelial cells. Interestingly, our lab has identified a correlation between increased microtubule plus end assembly rates in interphase cells and enhanced cell migration and invasion in colorectal cancer and melanoma cell lines suggesting that microtubule dynamics might be involved in the regulation of cancer cell migration and invasion. This Ph.D. thesis focused on the investigation of the role of supernumerary centrosomes on microtubule plus end assembly in melanoma and colorectal cancer cells and its involvement in paracrine signaling leading to increased microtubule growth rates and cell migration and invasion. I demonstrated that colorectal cancer and melanoma cells that exhibit increased microtubule plus end growth rates in interphase show increased cell migration and invasion. Moreover, rescue experiments demonstrated a requirement of increased microtubule dynamics for migration and invasion in these cancer cells. Interestingly, these cancer-associated phenotypes were accompanied by the presence of a high proportion of cells with supernumerary centrosomes. In fact, induction of supernumerary centrosomes was sufficient to trigger increased microtubule plus end assembly rates in interphase. Intriguingly, the ability to increase microtubule plus end assembly rates could be transferred onto non-invasive cells by paracrine signaling and this was found to be mediated by shedding microvesicles in a microtubule dynamics dependent manner. Finally, evidence was obtained that microvesicle-mediated increase of microtubule dynamics might involve HER2/ERK signaling. The data presented in this Ph.D. thesis indicate a requirement of abnormally increased microtubule dynamics for cancer cell migration and invasion and thus, for metastasis. Furthermore, the shedding of cancer-relevant microvesicles and the induction of paracrine signaling dependents on microtubule plus end assembly rates in interphase and seems to be associated with an increased activity of HER2/ERK signaling. Thus, inhibition of HER2/ERK signaling or direct suppression of microtubule dynamics, e.g., by the treatment with microtubule targeting drugs including Taxol, may offer new possibilities for targeting metastasis in human cancer.