Lasp-1 Signaling in Breast Carcinoma Cell Invasion/Migration

Institution: Scripps Research Institute
Investigator(s): Yi Hsing Lin, Ph.D. -
Award Cycle: 2001 (Cycle VII) Grant #: 7FB-0117 Award: $85,508
Award Type: Postdoctoral Fellowship
Research Priorities
Biology of the Breast Cell>Pathogenesis: understanding the disease

Initial Award Abstract (2001)
Lasp-1 is a gene that is linked to breast cancer in humans. Clinical studies indicate that the lasp-1 gene can be found in 8-12% breast cancer cells. We propose to study the mechanism by which lasp-1 gene induces the spread of the cancer cells from the primary site (i.e. breast) to distant sites within the body such as the lungs and bones. Since this is the primary reason that cancer patients die, it is important, scientifically, to understand how this gene causes the spread of cancer so that specific medical treatment can be developed to stop the spread of this disease and increase patient survival.

The hypotheses of our proposal are (i) Lasp-1 is a protein that plays an important role in breast cancer cell migration and invasion into surrounding tissues and distant sites. (ii) A region (s) of Lasp-1 protein is (are) responsible for the spread of breast cancer. Our preliminary data shows that Lasp-1 is involved in the spread of cancer cells and we hypothesized that a specific part of this protein is involved in this process. We have showed that overproduction of this protein in breast cancer cells increases the movement of the cells. We will also prove that this protein is necessary for the increase for the cell movement by blocking Lasp-1 production in cells. The region (s) of Lasp-1 that are important for cancer cell spreading will be determined by generating mutants defective in certain parts of the protein followed by functional migration and invasion studies.

We propose to investigate the role of Lasp-1 in breast cancer invasion, which has not been studied previously even though it was originally found to be over-produced in breast cancer cells. Results from the studies in this proposal will help define the role of protein signals in the development of metastatic breast cancer induced by Lasp-1. Such information may lead to the development of specific drugs or agents directed at blocking Lasp-1 and/or in downstream signals in breast cancer patients.

Final Report (2003)
Pseudopodia are temporary projection of cell membrane that cells use to move from one place to another. Large-scale proteomic and functional analysis of isolated pseudopodia revealed Lasp-1 as a novel protein necessary for cell migration, but not adhesion to the extracellular matrix. Lasp-1 is a ubiquitously expressed actin-binding protein with a unique domain configuration containing SH3 and LIM domains, and is overexpressed in 8-12% of human breast cancers.

We find that stimulation of non-motile and quiescent cells with growth factors or ECM proteins facilitates Lasp-1 relocalization from the cell periphery to the leading edge of the pseudopodium, where it associates with nascent focal complexes and areas of actin polymerization. Interestingly, while Lasp-1 dynamics in migratory cells occur independently of c-Abl kinase activity and tyrosine phosphorylation, c-Abl activation by apoptotic agents specifically promotes phosphorylation of Lasp-1 at tyrosine 171. This prevents Lasp-1 localization to focal adhesions leading to cell death.

Together these data demonstrate that Lasp-1 is a dynamic focal adhesion regulatory protein necessary for cell migration and survival in response to growth factors and ECM proteins.