E-cadherin, an epithelial-specific cell-cell adhesion molecule, plays multiple roles in maintaining adherens junctions, regulating migration and invasion, and mediating intracellular signaling. Downregulation of E-cadherin is a hallmark of epithelial-mesenchymal transition (EMT) and correlates with poor prognosis in multiple carcinomas. Conversely, upregulation of E-cadherin is prognostic for improved survival in sarcomas. Yet, despite the prognostic benefit of E-cadherin expression in sarcoma, the mechanistic significance of E-cadherin in sarcomas remains poorly understood. Here, by combining mathematical models with wet-bench experiments, we identify the core regulatory networks mediated by E-cadherin in sarcomas, and decipher their functional consequences. Unlike in carcinomas, E-cadherin overexpression in sarcomas does not induce a mesenchymal-epithelial transition (MET). However, E-cadherin acts to reduce both anchorage-independent growth and spheroid formation of sarcoma cells. Ectopic E-cadherin expression acts to downregulate phosphorylated CREB (p-CREB) and the transcription factor, TBX2, to inhibit anchorage-independent growth. RNAi-mediated knockdown of TBX2 phenocopies the effect of E-cadherin on p-CREB levels and restores sensitivity to anchorage-independent growth in sarcoma cells. Beyond its signaling role, E-cadherin expression in sarcoma cells can also strengthen cell-cell adhesion and restricts spheroid growth through mechanical action. Together, our results demonstrate that E-cadherin inhibits sarcoma aggressiveness by preventing anchorage-independent growth.
Background Radium-223 is a targeted alpha-particle therapy that improves survival in men with metastatic castration resistant prostate cancer (mCRPC), particularly in men with elevated serum levels of bone alkaline phosphatase (B-ALP). We hypothesized that osteomimicry, a form of epithelial plasticity leading to an osteoblastic phenotype, may contribute to intralesional deposition of radium-223 and subsequent irradiation of the tumor microenvironment. Methods We conducted a pharmacodynamic study (NCT02204943) of radium-223 in men with bone mCRPC. Prior to and three and six months after radium-223 treatment initiation, we collected CTCs and metastatic biopsies for phenotypic characterization and CTC genomic analysis. The primary objective was to describe the impact of radium-223 on the prevalence of CTC B-ALP over time. We measured radium-223 decay products in tumor and surrounding normal bone during treatment. We validated genomic findings in a separate independent study of men with bone metastatic mCRPC (n = 45) and publicly accessible data of metastatic CRPC tissues. Results We enrolled 20 men with symptomatic bone predominant mCRPC and treated with radium-223. We observed greater radium-223 radioactivity levels in metastatic bone tumor containing biopsies compared with adjacent normal bone. We found evidence of persistent Cellsearch CTCs and B-ALP (+) CTCs in the majority of men over time during radium-223 therapy despite serum B-ALP normalization. We identified genomic gains in osteoblast mimicry genes including gains of ALPL, osteopontin, SPARC, OB-cadherin and loss of RUNX2, and validated genomic alterations or increased expression at the DNA and RNA level in an independent cohort of 45 men with bone-metastatic CRPC and in 150 metastatic biopsies from men with mCRPC. Conclusions Osteomimicry may contribute in part to the uptake of radium-223 within bone metastases and may thereby enhance the therapeutic benefit of this bone targeting radiotherapy.
42E-cadherin, an epithelial-specific cell-cell adhesion molecule, plays multiple roles in maintaining 43 adherens junctions, regulating migration and invasion, and mediating intracellular signaling. 44 Downregulation of E-cadherin is a hallmark of epithelial-mesenchymal transition (EMT) and 45 correlates with poor prognosis in multiple carcinomas. Conversely, upregulation of E-cadherin is 46 prognostic for improved survival in sarcomas. Yet, despite the prognostic benefit of E-cadherin 47 expression in sarcoma, the mechanistic significance of E-cadherin in sarcomas remains poorly 48 understood. Here, by combining mathematical models with wet-bench experiments, we identify 49 the core regulatory networks mediated by E-cadherin in sarcomas, and decipher their functional 50 consequences. Unlike in carcinomas, E-cadherin overexpression in sarcomas does not induce a 51 mesenchymal-epithelial transition (MET). However, E-cadherin acts to reduce both anchorage-52 independent growth and spheroid formation of sarcoma cells. Ectopic E-cadherin expression acts 53 to downregulate phosphorylated CREB (p-CREB) and the transcription factor, TBX2, to inhibit 54 anchorage-independent growth. RNAi-mediated knockdown of TBX2 phenocopies the effect of 55 E-cadherin on p-CREB levels and restores sensitivity to anchorage-independent growth in 56 sarcoma cells. Beyond its signaling role, E-cadherin expression in sarcoma cells can also 57 strengthen cell-cell adhesion and restricts spheroid growth through mechanical action. Together, 58 our results demonstrate that E-cadherin inhibits sarcoma aggressiveness by preventing 59 anchorage-independent growth. 60 61 62 63 64 65 66 67 68 69 70 71Sarcomas -deadly cancers that arise from tissues of a mesenchymal lineage -are highly 72 aggressive, with five year survival rates of just 66% (1). Despite their mesenchymal origin, some 73 sarcomas undergo phenotypic plasticity in which they gain "epithelial-like" traits (2)(3)(4). While 74 this transition to a more epithelial-like state is now being recognized as a feature of multiple 75 subtypes of soft tissue sarcoma and osteosarcoma (2)(3)(4), there are also a number of sarcoma 76 subtypes that are classically known to exhibit epithelioid features pathologically, including 77 synovial sarcoma (5), epithelioid sarcoma (6), and adamantinoma (7). One might expect the 78 acquisition of epithelial-like traits to be of little relevance in mesenchymal tumors, yet that is not 79 the case. Phenotypic plasticity is clinically important in sarcoma patients: Sarcoma patients 80 whose tumors express epithelial-like biomarkers have improved outcomes relative to patients 81 with more "mesenchymal-like" tumors (2)(3)(4)8). 82 Phenotypic plasticity observed in sarcomas is reminiscent of the phenomenon of 83 epithelial plasticity in carcinomas. Epithelial plasticity refers to reversible transitions between 84 epithelial and mesenchymal phenotypes. In carcinomas, the phenotypic transition to a more 85 mesenchymal-like state via an epithelial-mesenchyma...
<p>S2. Ectopic E-cadherin expression in sarcoma cells does not alter EMT.</p>
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.