Stress granule formation enables anchorage-independence survival in cancer cells

Abstract

Stress granules (SGs) are dynamic cytoplasmic structures assembled in response to various stress stimuli that enhance cell survival under adverse environmental conditions. Here we show that SGs contribute to breast cancer progression by enhancing the survival of cells subjected to anoikis stress. SG assembly is triggered by inhibition of Focal Adhesion Kinase (FAK) or loss of adhesion signals. Combined proteomic analysis and functional studies reveal that SG formation enhances cancer cell proliferation, resistance to metabolic stress, anoikis resistance, and migration. Importantly, inhibiting SG formation promotes the sensitivity of cancer cells to FAK inhibitors being developed as cancer therapeutics. Furthermore, we identify the Rho-ROCK- PERK-eIF2 axis as a critical signaling pathway activated by loss of adhesion signals and inhibition of the FAK-mTOR-eIF4F complex in breast cancer cells. By triggering SG assembly and AKT activation in response to anoikis stress, PERK functions as an oncoprotein in breast cancer cells. Overall, our study highlights the significance of SG formation in breast cancer progression and suggests that therapeutic inhibition of SG assembly may reverse anoikis resistance in treatment-resistant cancers such as triple-negative breast cancer (TNBC). HighlightsO_LIEither anoikis stress or loss of adhesion induce stress granule (SG) formation C_LIO_LIThe Rho-ROCK-PERK-eIF2 axis is a crucial signaling pathway triggered by the absence of adhesion signals, leading to the promotion of SG formation along with the inhibition of the FAK- AKT/mTOR-eIF4F complex under anoikis stress. C_LIO_LIPERK functions as an oncogene in breast cancer cells, initiating SG formation and activating AKT under anoikis stress. C_LIO_LIInhibiting SG formation significantly enhances the sensitivity to Focal Adhesion Kinase (FAK) inhibitors, suggesting a potential for combined therapy to improve cancer treatment efficacy. C_LI