Pulmonary Lymphangioleiomyomatosis (LAM): The role of TSC2 in cell attachment

Six month visit by Dr Lyn M Moir to Dr Vera Krymskaya’s laboratory, University of Pennsylvania, Philadelphia, PA, USA 01 June – 30 November 2007

Summary

Pulmonary lymphangioleiomyomatosis (LAM) is a progressive and usually fatal rare lung disease which affects women of child bearing age predominantly. During the progression of the disease, abnormal smooth muscle-like cells known as LAM cells invade healthy lung tissue. Obstructing the airways, blood and lymph vessels, LAM cells prevent the lungs from functioning properly.

Scientific research over the past 10 years has shown that LAM is caused by genetic mutations in tuberous sclerosis complex 1 (TSC1) and TSC2. Loss of TSC2 function results in increased cell growth. The origin of LAM cells is not known but it is thought that these cells may migrate from another location.

Recent research has shown that cells which lack TSC2 migrate more, but the mechanisms involved are not well understood. In order for cells to move, they have to alter their shape and modify their attachment and spreading in the surrounding extracellular matrix (ECM) environment. Any change in cell attachment and/or spreading may contribute to the increased cell migration and invasiveness associated with LAM cells.

The research project I participated in involved examining the role of TSC2 in cell attachment and spreading. We found that cells which did not express TSC2 had increased attachment and spreading. We concluded that the lack of TSC2 may contribute to the altered migration associated with LAM cells.

As LAM progresses, cystic destruction of lung tissue occurs. In healthy bodies the degradation and replacement of lung tissue is a normal process which is regulated by a balance between enzymes known as matrix metalloproteinases (MMPs) and their inhibitors called tissue inhibitors of MMPs (TIMPs). If this balance is altered in any way, too much or too little tissue may be replaced, possibly altering cell function.

In LAM an increased amount of a particular MMP, called MMP-2, is present in the lungs. We found that the drug doxycycline, which can inhibit MMPs, also reduces cell spreading, suggesting that MMPs play an important role in cell adhesion and may contribute to the migration and metastasis associated with LAM disease.

The research project has enhanced our understanding of the mechanisms through which TSC2 may play a role in cell attachment, spreading and migration. Targeting TSC2 and/or MMPs may provide a therapeutic target for the control of cell migration and metastasis associated with LAM disease.