During metastatic colonisation tumour cells must establish a favourable microenvironment, or niche, that will sustain their growth. However, both the temporal and molecular details of this process are poorly understood.
Here, using breast cancer models, we find that metastatic initiating cells (MICs) in a mesenchymal phenotype exhibit high niche activation ability as a result of Thrombospondin 2 (THBS2) secretion, which prompts lung fibroblasts activation. Importantly, inhibiting the mesenchymal phenotype of MICs, by blocking the epithelial to mesenchymal transition (EMT)-associated kinase AXL during the early stages of cancer cell infiltration, reduces THBS2 secretion, niche activation ability, and consequently metastatic establishment. Subsequently, cancer cells start expanding at the target site and revert to a more epithelial phenotype. Interestingly, the activated fibroblasts of the newly formed metastatic niche trigger the reversion of cancer cell mesenchymal phenotype without compromising self-renewal. Preventing this phenotypic reversion by enhancing AXL expression during colonization block metastasis.
In summary, we demonstrate that during metastatic colonization the two events of niche activation and EMT are functionally linked at the target site. However, in this context, EMT becomes uncoupled from the ‘stemness’ required for metastatic growth. Further, once fibroblasts within the niche are activated they promote the mesenchymal to epithelial transition (MET) of tumour cells, leading to the outgrowth of metastases with similar epithelial characteristics and stromal cell networks to their original primary tumours.
Citation Format: Yaiza Del Pozo Martin, Danielle Park, Erik Sahai, Ilaria Malanchi. Mesenchymal status promotes metastatic colonization via a cancer cell-stroma crosstalk which uncouples EMT and stemness. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4723. doi:10.1158/1538-7445.AM2015-4723