Cytoskeletal Regulation of Cancer Stem Cell Metastatic Potential

Cancer stem cells (CSCs), a tumour cell subpopulation with the ability to self-renew and give rise to non stem cancer cells, have been identified in multiple malignancies and are thought to be responsible for most cancer relapses and treatment resistance. In breast cancer, a high degree of stemness has been associated with undifferentiated tumours and poor prognosis. Interestingly, acquisition of an invasive phenotype via epithelial to mesenchymal transition

(EMT) induces stemness properties (1), suggesting a functional link between acquisition of mesenchymal traits and stemness programs in breast cancer. Indeed CSCs, which were found to initiate metastatic colonization in breast cancer models (2), were found to be in an EMT status (Malanchi unpublished data). Remarkably, TGF-beta triggered EMT in carcinoma cells via RhoA-ROCK activation, a known mediator of actomyosin contractility. Interestingly, melanoma, which retains high level of tumour cell spreading, also retains high levels of stem-cell content. Invasive melanoma cells in an elongated-mesenchymal state can change their mode of migration by adopting a rounded-amoeboid mode of movement through increasing their Rho-driven cytoskeletal actomyosin. Recently it has been shown that the transition from elongated-mesenchymal to amoeboid mode of movement (MAT) in melanoma cells is characterized by increased stemness (3).Morover, Dr Victoria Sanz-Moreno laboratory (King’s College London), has described how the stemness modulators LIF-JAK-STAT3 regulate rounded-amoeboid invasive mode in vitro and in vivo by ROCK activation in melanoma cells and this is particularly prominent at tumour margins (4, 5). Taken together, these data suggest that increasing the level of contractility in cancer cells, via EMT in carcinoma cells or via MAT in melanoma cells, correlates with a gain in stemness programs (1, 3). Therefore, we hypothesise a molecular link between the pathways regulating both migration and stemness abilities, which will be maintained across tumour types (from carcinoma to melanoma). Importantly, work in the Malanchi and Sanz-Moreno laboratories has generated a signature correlating the genes enriched in melanoma amoeboid cells (MAT transition) and the gene of breast cancer metastatic CSCs in an EMT status. This common gene expression signature is composed of approximately 100 genes and will be called “Cytoskeletal-Contractile Stem Cell signature” (C-ConSC signature).

The main goal of this project is to increase our understanding of metastatic dissemination and resistance to therapies in cancer patient relapse, attempting to connect current theories on EMT and CSCs and understand the links with the cytoskeleton. The high level of correlation between the signatures of carcinoma CSCs and highly contractile melanoma cells observed by our laboratories suggests for the first time the invasion/stemness crosstalk to be a common crucial feature to all tumour types. More importantly, this will allow us to identify key important genes regulating both CSC traits and metastatic spread resolving a major problem in cancer biology.

Refs:

1. The epithelial-mesenchymal transition generates cells with properties of stem cells.

2. Interactions between cancer stem cells and their niche govern metastatic colonization.

3. Mesenchymal to amoeboid transition is associated with stem-like features of melanoma cells.

4. Cell Commun Signal ROCK and JAK1 signaling cooperate to control actomyosin contractility in tumor cells and stroma.

Дата добавления: 2015-10-29