Fellow's research: An atypical cell-cell adhesion protein that inhibits cancer metastasis


09 May 2019

Fellow's research: An atypical cell-cell adhesion protein that inhibits cancer metastasis

 

Dr Sabyasachi Rakshit, Intermediate Fellow

Indian Institute of Science Education and Research Mohali

Recent study from my research group shows that Cadherin-23, an atypical cell-cell adhesion protein of epithelial tissues, significantly suppresses cancer metastasis.

Cancer metastasis or spread of cancer cells from the primary tumour site to other parts of the body or a secondary tumour site is the primary cause of death in many cancers. The cell-cell junction described in textbooks predominantly has classical or typical cadherins. We observed that an atypical cadherin, Cadherin-23, which is produced in various tissues in relatively low amounts than the typical cadherins, mediates strong cell-cell aggregation and suppresses metastasis by inhibiting cell migration. Our observations correlate the survival of patients with cancer where low-expression of Cadherin-23 depicts more spread of cancer cells in secondary tissues and low survival of patients.  

In this study, we first analysed the patient data and correlated the production of Cadherin-23 proteins with metastasis and patient survival. Next, we estimated and compared the quantity of Cadherin-23 produced in normal and tumour tissues and cell lines and monitored how the change in protein production regulated cell migration, proliferation, invasion, and aggregation in cell lines. We also probed the mechanism of downregulation using epigenetic analysis.

The low expression of Cadherin-23 observed in cancer cells (like lung and oesophageal cancer cells) is caused by DNA-methylation that weakens cell-cell contacts and facilitates faster migration of cancer cells from primary to secondary sites (i.e., metastasis). Additionally, tumour cells also release the shorter isoforms of Cadherin-23 that block cell-cell adhesion further enhancing the cancer cell migration to other sites in the body.

Since Cadherin-23 is a metastasis-suppressor, developing biochemical strategies of de-methylation of DNA can re-install cadherin-23 at the cell-cell junctions and fix cancer cells at the primary sites. This will certainly aid the treatment of the tumour and extend patient-survival significantly. Cadherin-23, especially its soluble isoforms, can serve as a prognostic marker in cancer.

Cadherin-23 (Cdh23, in dark red), a long chain non-classical cadherin, is uniformly expressed in different normal tissues (in blue) and mediates strong cell-cell adhesion junctions. It is down-regulated in cancer cells (in red) by promoter methylation and produces soluble isoforms (in green) which disrupt the cell-cell attachment leading to increased migration.

Reference:

The strong propensity of Cadherin23 for aggregation inhibits cell migration. Malay K. Sannigrahi, Cheerneni S. Srinivas, Nilesh Deokate, Sabyasachi Rakshit. Molecular Oncology, February 2019

Banner Credits: Lung cancer cells. Anne Weston, Francis Crick Institute. CC BY-NC