Tissue Stiffness and Hypoxia Modulate the Integrin-Linked Kinase ILK to Control Breast Cancer Stem-like Cells

Abstract

Breast tumors are stiffer and hypoxic compared to nonmalignant breast tissue. Here we report that stiff and hypoxic microenvironments promote the development of breast cancer stem-like cells (CSC) through modulation of the integrin-linked kinase ILK. Depleting ILK blocked stiffness and hypoxia-dependent acquisition of CSC marker expression and behavior, whereas ectopic expression of ILK stimulated CSC development under softer or normoxic conditions. Stiff microenvironments also promoted tumor formation and metastasis in ovo, where depleting ILK significantly abrogated the tumorigenic and metastatic potential of invasive breast cancer cells. We further found that the ILK-mediated phenotypes induced by stiff and hypoxic microenvironments are regulated by PI3K/Akt. Analysis of human breast cancer specimens revealed an association between substratum stiffness, ILK and CSC markers, insofar as ILK and CD44 co-localized in cancer cells located in tumor regions predicted to be stiff. Our results define ILK as a key mechanotransducer in modulating breast CSC development, in response to tissue mechanics and oxygen tension.

Revisiting Seed and Soil: Examining the Primary Tumor and Cancer Cell Foraging in Metastasis

“…Variance in these physical conditions may determine whether the environment is conducive for cell movement. For example, the ECM may facilitate cell motility by providing a stiff substrate for cellular focal adhesion necessary for cell movement (38). Conversely, the ECM structure and organization can inhibit movement depending on characteristics such as fiber composition and alignment (39).…”

From transformation to metastasis: deconstructing the extracellular matrix in breast cancer

“…Presence of hypoxia is correlated with poor prognosis and treatment resistance in breast cancer patients [100]. Recently, it was shown that hypoxic and stiff breast tumors promote proliferation of breast cancer stem-like cells [101], which, in turn, can mediate resistance to therapy [102]. …”

Matrix stiffness mediates stemness characteristics via activating the Yes‐associated protein in colorectal cancer cells

“…Biophysical cues in the tumor microenvironment are considered to be key and novel regulators of CSC maintenance and tumorigenic potential. In breast cancer cells and hepatocellular carcinoma cells, increasing the matrix stiffness of tumor cells can upregulate the expression of CSC biomarkers and self‐renewal ability. We cultured the CRC cell line HCT‐116 in a stiffness gradient of culture matrix and found that the mRNA and protein levels of the CSC biomarkers increased with the increased stiffness of culture matrix.…”

“…Studies have shown that extracellular matrix (ECM) stiffness is part of the physical microenvironment of tumor cells. The extracellular physical signals are transformed into intracellular biological signals through the “extracellular matrix‐cell membrane receptor‐intracellular molecule” pathway, also called the “mechanical‐biological” signal transduction pathway, and this transformation plays an important role in screening and maintaining the CSC phenotype . It has been proven that the integrin family acts as a switch, and Yes‐associated protein (YAP) is a key molecule in this pathway …”