CEACAM1 controls the EMT switch in murine mammary carcinomain vitroandin vivo

Abstract

We analyzed the molecular basis for carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1)-controlled inhibition of epithelial-mesenchymal transition (EMT) in a mouse model for mammary adenocarcinoma (WAP-T mice). We demonstrate that silencing of CEACAM1 in WAP-T tumor-derived G-2 cells induces epithelial-mesenchymal plasticity (EMP), as evidenced by typical changes of gene expression, morphology and increased invasion. In contrast, reintroduction of CEACAM1 into G-2 cells reversed up-regulation of genes imposing mesenchymal transition, as well as cellular invasion. We identified the Wnt-pathway as target for CEACAM1-mediated repression of EMT. Importantly, β-catenin phosphorylation status and transcriptional activity strongly depend on CEACAM1 expression: CEACAM1high G-2 cells displayed enhanced phosphorylation of β-catenin at S33/S37/T41 and decreased phosphorylation at Y86, thereby inhibiting canonical Wnt/β-catenin signaling. We identified Src-homology 2 domain-containing phosphatase 2 (SHP-2) as a critical binding partner of CEACAM1 that could modulate β-catenin Y86 phosphorylation. Hence, CEACAM1 serves as a scaffold that controls membrane proximal β-catenin signaling. In vivo, mammary tumors of WAP-T/CEACAM1null mice displayed increased nuclear translocation of β-catenin and a dramatically enhanced metastasis rate compared to WAP-T mice. Hence, CEACAM1 controls EMT in vitro and in vivo by site-specific regulation of β-catenin phosphorylation. Survival analyses of human mammary carcinoma patients corroborated these data, indicating that CEACAM1 is a prognostic marker for breast cancer survival.

Tumor intrinsic immunity related proteins may be novel tumor suppressors in some types of cancer

“…The absence of CEACAM1 on hyperplastic tumors correlated with reduced apoptosis of malignant cells 52 . Moreover, CEACAM1 knockout mice lacking CEACAM1 in WAP-T tumor cells had enhanced tumor phenotypes including increased Wnt signaling, promoted cellular invasiveness, and strongly enhanced rate of metastasis of mammary adenocarcinomas in vivo 78 . Miska et al .…”

Characterization of murine CEACAM1 in vivo reveals low expression on CD8+ T cells and no tumor growth modulating activity by anti-CEACAM1 mAb CC1

“…Stable expression of CEACAM1 on melanoma cells enhanced invasion and migration of the cells in vitro [9] Reduced expression of CEACAM1 was reported upon malignant transformation in mice [10] and in samples of human colorectal cancer [11]. Similarly, CEACAM1 expression inversely correlated with survival of breast cancer patients [8]. Frequent loss of CEACAM1 in benign and malignant colorectal neoplasias was also reported [7].…”

“…Nittka et al found that the Research Paper www.oncotarget.com absence of CEACAM1 on hyperplastic tumors correlated with reduced apoptosis of malignant cells [7]. Moreover, a lack of CEACAM1 in WAP-T tumor cells resulted in increased Wnt signaling, promoted cellular invasiveness, and strongly enhanced the rate of metastasis of mammary adenocarcinomas in vivo [8]. On the other hand, other investigations have suggested a role for CEACAM1 in angiogenesis and suppression of the neoantigen-specific anti-tumor response [3].…”

Size Matters: The Functional Role of the CEACAM1 Isoform Signature and Its Impact for NK Cell-Mediated Killing in Melanoma

“…Following intra-and extravasation of the vascular system, tumor cells need to have the potential to adapt and survive in the foreign environment of distant organs, where they can then form micro- and finally macro-metastases [75,76]. Significantly, CEACAM1 was also shown to control the epithelial-mesenchymal transition by site-specific regulation of beta-catenin [77]. Therefore, extensive efforts have been made to understand the molecular and cellular mechanisms driving the metastatic cascade with the aim of developing new therapeutic approaches against disseminated cancer cells.…”