Scripps researchers illuminate cancer cells’ survival strategy during dangerous dissemination

A team led by scientists at The Scripps Research Institute has discovered key elements of a strategy commonly used by tumour cells to survive when they spread to distant organs. The finding could lead to drugs that could inhibit this metastasis in patients with tumors.

A cell that breaks away from the primary tumour and finds itself in the alien environment of the bloodstream or a new organ, normally is destroyed by a process known as apoptosis. But tumour cells that express high levels of a certain surface protein are protected from apoptosis, greatly enhancing their ability to colonise distant organs. How this protein blocks apoptosis and promotes metastasis has been a mystery - until now.

''What we found in this study is that it's not the increased expression of the protein per se that protects a tumour cell, but, rather, the cleavage of this protein by proteolytic enzymes,'' said Scripps research Professor James P Quigley. ''This cleavage triggers a signalling cascade in the tumour cell that blocks apoptosis.'' Quigley is the principal investigator for the study, which was recently published online before print by the journal Oncogene.

''We think that a reasonable strategy for inhibiting metastasis would be to try to prevent the cleavage of this surface protein using antibodies or small-molecule drugs that bind to the cleavage site of the protein,'' said Elena I. Deryugina, a staff scientist in Quigley's laboratory and corresponding author of the manuscript.

A protein linked to poor outcome
The cell-surface protein at the centre of this research is known as CUB domain containing protein 1 (CDCP1). In 2003, a post-doctoral fellow in Quigley's laboratory, John D Hooper, discovered and co-named CDCP1 as a ''subtractive immunization metastasis antigen,'' also finding that it is highly expressed on the surfaces of metastasis-prone human tumor cells.

Quigley's laboratory and others soon found additional evidence that CDCP1 plays a major role in enabling metastasis. Clinical studies reported CDCP1 on multiple tumor types and linked its presence to worse outcomes for patients.