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The mesenchymal status of metastatic cancer cells promotes a stromal crosstalk leading to epithelial re-acquisition and metastatic colonisation

Del Pozo Martin, Y; (2015) The mesenchymal status of metastatic cancer cells promotes a stromal crosstalk leading to epithelial re-acquisition and metastatic colonisation. Doctoral thesis , UCL (University College London). Green open access

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Abstract

Solid epithelial tumours are complex structures in which the associated stroma supports cancer cells (Quail and Joyce, 2013). During metastatic progression, cancer cells disseminate from their tissue of origin and recapitulate the tumour structure at distant organs, including the stromal compartment. Metastasis initiating cells (MICs) are functionally discriminated among the bulk of cancer cells for their high ability to establish metastasis (Malanchi et al., 2012, Baccelli et al., 2013). Additionally, efficient metastasis requires the expression of specific molecules within the local microenvironment (Oskarsson et al., 2014). Thus, a favourable microenvironment or niche is a crucial early step in metastatic progression. However what features of MICs mediate metastatic niche activation is poorly characterised. One strategy adopted by metastatic cells to disseminate from primary tumours is the activation of the developmental programme epithelial-to-mesenchymal transition (EMT). However, EMT is a reversible programme that needs to be inhibited at the target site for tumour cells to re-acquire epithelial characteristics compatible with metastatic outgrowth (Nieto, 2013). To successfully metastasise cancer cells need to retain self-renewal and growth properties through epithelial plasticity. This implies that during metastasis ‘stemness’ should not be strictly coupled to EMT as previously suggested (Mani et al., 2008). To date, both the potential advantage of disseminated cancer cells mesenchymal status and the source of their epithelial plasticity at the metastatic site remain unknown. In this thesis we use metastatic breast cancer models to elucidate the enhanced niche-induction ability of mesenchymal MICs, its relationship to EMT and the source of its epithelial modulation during metastatic colonisation. Importantly, we identify THBS2 as a novel effector linked to the EMT status of cancer cells that enhances stromal niche activation. Subsequently, the newly activated stroma triggers cancer cell BMP-dependent re-epithelialisation promoting metastatic outgrowth. Thereby, we describe a temporally controlled metastatic colonisation where the EMT status of cancer cells promotes its own inhibition via a cancer cell-stromal crosstalk that initially enhances metastatic niche formation, and ultimately favours a cancer cell proliferative state compatible with metastatic outgrowth.

Type: Thesis (Doctoral)
Title: The mesenchymal status of metastatic cancer cells promotes a stromal crosstalk leading to epithelial re-acquisition and metastatic colonisation
Event: University College London
Open access status: An open access version is available from UCL Discovery
Language: English
Keywords: Metastasis, Breast Cancer, Metastatic Niche
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
URI: https://discovery.ucl.ac.uk/id/eprint/1473399
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