Converting Invasive Breast Cancer Cells Into Adipocytes Inhibits Cancer Metastasis

Introduction

Cancer cell plasticity facilitates the development of therapy resistance and malignant progression. Dedifferentiation processes such as epithelial-to-mesenchymal transition (EMT) enhance cellular plasticity facilitating in drug resistance and metastasis formation. Here, we hypothesize that a moment of cellular plasticity during cancer dissemination can be exploited therapeutically by forcing the trans-differentiation of breast cancer cells into post-mitotic adipocytes to inhibit cancer metastasis.

Material and method

Using established EMT models of murine mammary cancer cells, we studied the adipogenesis trans-differentiation potential of EMT-derived cancer cells versus their epithelial ancestors. We utilized established methods from adipogenesis studies to morphologically and functionally characterize cancer-derived adipocytes in vitro. The kinetics and gene expression regulation during cancer cell adipogenesis were analyzed based on RNA sequencing. Analysis of TGFβ signaling pathway activation during adipogenesis of cancer cells revealed clinically relevant targets for the induction of adipogenesis in vivo.

Delineation of the molecular pathways underlying such trans-differentiation has motivated a combination therapy with a MEK inhibitor and a PPARγ ligand in various mouse models of murine and human breast cancer in vivo. Direct cancer cell- adipogenesis, primary tumour invasiveness and metastasis formation were analyzed. To test the effect of adipogenic trans-differentiation as therapeutic option for breast cancer, we used apatient-derived xenograft (PDX) mouse model of human breast cancer in preclinical settings.

Results and discussion

Our results emphasize that cancer cells undergoing EMT gain trans-differentiation potential and can undergo cellular conversion into post-mitotic and functional adipocytes. Epithelial cancer cells lack this potential, supporting the notion that an EMT coincides with increased cell plasticity. In various preclinical mouse models, acombination therapy of FDA-approved drugs provoked the conversion of invasive and disseminating cancer cells into post-mitotic adipocytes leading to the repression of primary tumor invasion and metastasis formation.

Conclusion

The results underscore the pivotal role of cancer cell plasticity in malignant tumor progression and reveal the therapeutic potential that lies in the inhibition of cellular plasticity by forcing post-mitotic adipogenesis.