Decoding the Role of Caveolin-1 in Morphological Diversity and Self-Renewal of Breast Cancer Cells

Cellular geometry is tightly associated with the function of a cell. During tumour progression, cancer cells undergo changes in phenotypes and biological behaviour with deformations in cellular morphology. However, whether the morphological diversity of cancer cells correlates with the cellular phenotype, and the underlying mechanism of morphology-related function in cancer cells is still unclear. Here, we simplified the cellular morphology by clustering cancer cells into three categories based on two-dimensional cellular morphological features. The silence of caveolin-1 (Cav-1), the primary constituent of membrane caveolae, reproduced the morphological evolutionary behaviour of cancer cells, which is similar to the epithelial-mesenchymal transition process. The attenuation of dorsal stress fibres, the assembly of focal adhesions and the disorder of transverse arc fibres and their regulatory signals are demonstrated as the main morphological evolutionary tools of cancer cells. Moreover, a modified vertex model theoretically reconfirmed the evolutionary process of cellular morphology. Small GTPases and focal adhesion kinase signalling were implicated in Cav-1 knockdown-induced cytoskeletal remodelling and focal adhesion assembly. Both in vitro and in vivo studies have demonstrated that Cav-1-dependent morphological changes are closely associated with the self-renewal capacity of breast cancer cells. Overall, our work highlights new insight into the morphological diversity and the correlation between cellular shape and phenotype of cancer cells, and provides evidence that Cav-1 could affect cancer cell properties such as self-renewal capacity through maintaining the morphological stability.