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Pre-metastatic niche drives breast cancer invasion by modulating MSC homing and CAF differentiation
bioRxiv - Cancer Biology Pub Date : 2021-01-13 , DOI: 10.1101/2021.01.12.426460 Neha Saxena , Garvit Bhardwaj , Sameer Jadhav , Hamim Zafar , Shamik Sen
bioRxiv - Cancer Biology Pub Date : 2021-01-13 , DOI: 10.1101/2021.01.12.426460 Neha Saxena , Garvit Bhardwaj , Sameer Jadhav , Hamim Zafar , Shamik Sen
The extent to which cancer-associated alterations in extracellular matrix stiffness influences the crosstalk between cancer cells and mesenchymal stem cells (MSCs) remains unclear. By analyzing multiple single- cell RNA sequencing datasets, we establish the existence of a cell sub-population co-expressing MSC and cancer associated fibroblast (CAF) markers in highly aggressive triple-negative breast cancers in primary tumor, secondary sites, and in circulatory tumor cell clusters. Using hydrogels of varying stiffness corre- sponding to different stages of cancer progression, we show that on pre-metastatic stroma mimetic 2 kPa gels, MDA-MB-231 breast cancer cell secreted conditioned media drives efficient MSC chemotaxis and induces stable CAF differentiation in a TGFβ/contractility-dependent manner. In addition to enhancing cancer cell proliferation, 2 kPa CAFs maximally boost local invasion and confer resistance to flow-induced shear stresses. Together, our results suggest that homing of MSCs at the pre-metastatic stage and their differentiation into CAFs actively drives breast cancer invasion and metastasis.
更新日期：2021-01-14
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