AmotL2 disrupts apical–basal cell polarity and promotes tumour invasion

Abstract

The establishment and maintenance of apical-basal cell polarity is essential for the functionality of glandular epithelia. Cell polarity is often lost in advanced tumours correlating with acquisition of invasive and malignant properties. Despite extensive knowledge regarding the formation and maintenance of polarity, the mechanisms that deregulate polarity in metastasizing cells remain to be fully characterized. Here we show that AmotL2 expression correlates with loss of tissue architecture in tumours from human breast and colon cancer patients. We further show that hypoxic stress results in activation of c-Fos-dependent expression of AmotL2 leading to loss of polarity. c-Fos/hypoxia-induced p60 AmotL2 interacts with the Crb3 and Par3 polarity complexes retaining them in large vesicles and preventing them from reaching the apical membrane. The resulting loss of polarity potentiates the response to invasive cues in vitro and in vivo in mice. These data provide a molecular mechanism how hypoxic stress deregulates cell polarity during tumour progression.

Commitment of Scaffold Proteins in the Onco-Biology of Human Colorectal Cancer and Liver Metastases after Oxaliplatin-Based Chemotherapy

“…Deregulated AmotL2 expression in tumor and metastasized areas during tumor progression confirms what recently has been well established in colon cancer tumors, AmotL2 expression correlates with loss of polarity by means of hypoxia activated c-Fos, leading to loss of tissue architecture [11]. The complex c-Fos/hypoxia-induced p60 and AmotL2 interacting with the Crb3 and Par3 polarity complexes retain them in large vesicles, impeding them from reaching the apical membrane [11] and being involved, this way, in EMT.…”

“…Human AmotL2 encodes two isoforms of a molecular mass of 100 and 60 kDa [10]. Most human cancers have an epithelial origin and the assessment of malignancy is based on the loss of apicalbasal polarity of the epithelial organization (epithelial mesenchymal transition (EMT)); however, whether this is a cause or consequence of tumor progression has yet to be established [11]. Loss of polarity, EMT and angiogenesis are crucial in CRC.…”

CRB3 downregulation confers breast cancer stem cell traits through TAZ/β-catenin

“…These heterogeneous acinar structures were easily distinguishable from those formed by control cells, indicating that CRB3 downregulation disrupted the epithelial polarity of MCF 10A cells cultured in 3D. Polarity was also assessed using the localization of Golgi marker GM130 29, 30, 31 and epithelial marker E-cadherin. 32, 33 The orientation of the Golgi apparatus was monitored by staining GM130, a cytosolic coiled-coil protein anchored to Golgi membranes.…”

Mechanisms of Cell Polarity–Controlled Epithelial Homeostasis and Immunity in the Intestine

“…Further, hypoxic stress signaling resulted in the angiomotin-mediated retention of Par3 and Crumbs3 in intracellular vesicles and prevented these proteins from reaching the apical cell surface. The resulting loss of cell polarity potentiated the response to invasive cues, both in vitro in intestinal epithelial Caco-2 cells and in vivo in mice (Mojallal et al 2014). Par6 was reported to play a role in the directional (i.e., polarized migration of IEC as part of the intestinal wound healing response [Koch et al 2009]).…”