Inhibition of the membrane repair protein annexin-A2 prevents tumour invasion and metastasis

Abstract

Cancer cells are exposed to major compressive and shearing forces during invasion and metastasis, leading to extensive plasma membrane damage. To survive this mechanical stress, they need to repair membrane injury efficiently. Targeting the membrane repair machinery is thus potentially a new way to prevent invasion and metastasis. We show here that annexin-A2 (ANXA2) is required for membrane repair in MDA-MB-231 cells, a highly invasive triple-negative breast cancer cell line. Mechanistically, we show by fluorescence and electron microscopy that cells fail to reseal membrane damaged by shear stress when ANXA2 is silenced or the protein is inhibited with neutralizing antibody. Silencing of ANXA2 has no effect on proliferation in vitro, and even accelerates migration in wound healing assays, but reduces tumor cell dissemination in both mice and zebrafish. We show that high expression of ANXA2 predicts poor prognosis in high-grade lung, ovarian, gastric and breast cancers. We expect that inhibiting membrane repair will be particularly effective in these aggressive, poor prognosis tumors because they rely on the membrane repair machinery to survive membrane damage during tumor invasion and metastasis. This could be achieved either with monoclonal anti-ANXA2 antibodies, which have been shown to inhibit metastasis of MDA-MB-231 cells, or with small molecule drugs.

Versatile roles of Annexin A4 in ccRCC: impact on membrane repair, transcriptional signatures, and composition of the tumor microenvironment

“…45 This has recently led to the concept that acute membrane repair might also be centrally involved in the cascade of essential mechanisms required in metastasis and resistance to cytotoxic immune cells. 46,47 Our observations that ANXA4 is modulating membrane repair of renal carcinoma cells (Figure 3), is in line with previous studies investigating the general capacity of annexin proteins to reseal and repair damaged plasma membranes (including ANXA6, ANXA5 and ANXA2). 46,48,49 Remarkably, the potential of ANXA4 for membrane repair appears not to be limited to cancer cells, as it was recently demonstrated that ANXA4 is also involved in the pathogenesis of glaucoma via mediating modes of membrane repair under biophysical strain conditions.…”

“…46,47 Our observations that ANXA4 is modulating membrane repair of renal carcinoma cells (Figure 3), is in line with previous studies investigating the general capacity of annexin proteins to reseal and repair damaged plasma membranes (including ANXA6, ANXA5 and ANXA2). 46,48,49 Remarkably, the potential of ANXA4 for membrane repair appears not to be limited to cancer cells, as it was recently demonstrated that ANXA4 is also involved in the pathogenesis of glaucoma via mediating modes of membrane repair under biophysical strain conditions. 50 Thereby, these observations complete our understanding of the general involvement of ANXA4 in the process of membrane repair, and further demonstrate the versatile localization modes related to extracellular and tumor inherent features.…”

Annexin‐A5 and annexin‐A6 silencing prevents metastasis of breast cancer cells in zebrafish

“…Inhibiting membrane repair of cancer cells with therapeutic antibodies would be a good option since it has been shown that a monoclonal anti‐ANXA6 antibody significantly decreases the invasiveness of pancreatic, lung, and breast cancer cells in vitro (O'Sullivan et al., 2017). In addition, we and other have shown that anti‐ANXA2 antibodies may affect membrane repair in cancer cells and prevent tumor growth and metastasis (Gounou et al., 2022; Lokman et al., 2013). Mechanistically, we hypothesize that antibodies enter the cell at sites of membrane damage and interfere with the membrane repair machinery.…”

“…Nevertheless, they contradict a previous study of Vila de Muga et al., in which it was reported that ANXA6 expression is lower in ER‐negative compared ER‐positive breast cancer cell lines (Vilá de Muga et al., 2009). Interestingly, we recently reported that ANXA1 and ANXA2 were also expressed at higher level in MDA‐MB‐231 compared to MCF7 cells (Gounou et al., 2022), suggesting that stronger invasive properties were associated with higher expression of membrane repair proteins. Nevertheless, we could not rule out the possibility that another cell process, such as cell growth, proliferation, motility, or lipid/glucose homeostasis, may be dysregulated and explain modified invasiveness (Grewal et al., 2021).…”