LAP1 supports nuclear plasticity during constrained migration

Abstract

Metastatic spread involves the dissemination of cancer cells from a primary tumour and their colonisation of distal sites. During this process, cancer cells must negotiate multiple physical constraints imposed by the microenvironment and tissue structure, and the biophysical properties of the nucleus place a physical challenge on this form of migration. By analysing nuclear genes upregulated during the acquisition of metastatic potential, we discovered increased expression of the inner nuclear membrane protein LAP1 in metastatic cell lines and at the leading edge of human primary tumours and in metastatic lesions. Human cells express two LAP1 isoforms (LAP1B and LAP1C), which differ in their amino terminus. We found that the longer isoform, LAP1B, binds more strongly to nuclear lamins and enhances nuclear mechanocoupling, whilst the shorter isoform, LAP1C, favours nuclear envelope blebbing and permits migration through physical constraints. Thus, we propose that LAP1B and LAP1C act together to support a permissive nucleus which overcomes the physical constraints that cancer cells face during metastatic spread.