Dysadherin: a new player in cancer progression

Abstract

Dysadherin is a cancer-associated cell membrane glycoprotein that promotes experimental cancer metastasis. Here we review recent work that has provided insights into possible mechanisms of action of this newly recognized player in the cancer progression process. Dysadherin modulates cell phenotype in a number of ways, including down-regulation of E-cadherin-mediated cell adhesion, and up-regulation of chemokine production. In this way, expression of dysadherin in a tumor can influence both the tumor cell itself and the stromal compartment, so as to create conditions that are more permissive for metastatic spread. Dysadherin expression is also an independent prognostic indicator of metastasis and survival for many different types of human cancer. Thus, dysadherin may represent a new molecular target for the visualization, prevention or treatment of advanced cancer.

Fig. 1. Dysadherin structure, and a model for the role of dysadherin in cancer progression

A. Primary sequence and domain structure for human dysadherin. Dysadherin is a single-pass transmembrane protein of 178 amino acids, with a long extracellular domain, a transmembrane domain and a short cytoplasmic tail. The highest conservation between FXYD family members lies in the region of the FXYD motif and the transmembrane domain. Residues that are absolutely conserved between all family members are shown in red. The extracellular domain is heavily and heterogeneously glycosylated, carrying up to 30KDa of O-linked carbohydrate in some tumor cells. B. Model for dysadherin action. Dysadherin predominantly resides in the plasma membrane. There is convincing evidence that dysadherin can reduce cell-cell adhesion by blocking expression of E-cadherin at a post-transcriptional level, and/or by down-regulating the association of E-cadherin with the actin cytoskeleton. Dysadherin can also affect invasion and metastasis by E-cadherin-independent mechanisms. One such mechanism involves upregulating expression of the chemokine CCL2, which then exerts autocrine and paracrine tumor-promoting effects in the tumor bed. The detailed molecular mechanisms that couple dysadherin expression to down-stream events that promote tumor progression are currently not known. However, dysadherin expression is associated with enhanced activity of the NFκB pathway in a breast cancer model system. In non-transformed cells, dysadherin interacts with and modulates the activity of the Na+,K+-ATPase. It remains to be determined whether this interaction occurs in tumor cells or what the functional consequences may be. Finally, it is likely that dysadherin also regulates the activity of additional downstream effector molecules (indicated by X) that have yet to be identified.

Figure 2. Dysadherin expression in oncogene transformed breast epithelial cells and clinical breast cancer samples, from in silico datamining of published expression array data

A. Dysadherin mRNA is upregulated in human breast epithelial cells transformed by several different oncogenes. Data were derived by datamining expression array results in [6]. β-Cat: activated β-catenin. * P<0.05 when compared with untransformed control cells. B. Dysadherin mRNA is upregulated in estrogen receptor (ER) negative compared with ER positive breast cancer samples (datamining from clinical microarray results in [30]). C. Dysadherin mRNA is upregulated in breast cancers with mutations in the BrCa1 gene when compared with sporadic breast cancers (datamining from clinical microarray results in [31]). N indicates the number of patients in each clinical subgroup.

Figure 3. Endogenous dysadherin is required for efficient metastasis of human breast cancer cells

A. Schematic of experimental design. B. Functional knockdown of dysadherin in MDA-MB231 human breast cancer cells using siRNA results in decreased metastasis to the lungs following injection of genetically modified cells into the tail vein of nude mice (see [9]).