Project Summary. Pulmonary lymphangioleiomyomatosis (LAM) is metastatic, understudied sarcoma, which
predominantly affects women, and manifests as proliferation of tumor smooth muscle-like cells within the
lungs. LAM is caused by TSC1/2 loss of function mutations that lead to mTOR hyperactivation, therefore,
mTOR inhibitor rapamycin is approved for LAM. However, although rapamycin stabilizes the lung function,
after therapy cessation the progressive decline in the lung function resumes leading to respiratory insufficiency
and there are no other drugs approved for LAM. Thus, the discovery of new therapeutic targets for LAM is
critically needed.
The objectives of this project are: (1) determine a role of extracellular vesicles (EV) in LAM metastasis and (2)
provide the proof-of-concept for targeting EV for LAM.
A role of EV in LAM has not yet been explored, however, our published and preliminary studies indicate that
(a) EV cargo contribute to LAM metastasis via enhancing cancer stem-cell (CSC) characteristics and survival
of circulating LAM cells and lung remodeling and (b) rapamycin affects EV, possibly, leading to enhanced
seeding of the lungs by LAM cells.
These data lead to our central hypothesis that TSC1/2-null-cell-derived EV cargo, containing SOX-10,
integrins, and c-Src, increases LAM metastasis via increasing CSC plasticity and survival of circulating LAM
cells and via lung extracellular matrix (ECM) remodeling mediated by resident lung fibroblasts, which enhances
lung seeding by LAM cells. Rapamycin enhances EV production by TSC1/2-null cells and their quality, which
may explain faster clearance of LAM cells from the circulation of patients treated with rapamycin analogs but
simultaneously and adversely enhances LAM lung metastasis. A key translational corollary of this hypothesis is
that LAM will be sensitive to inhibition of the EV pathway and targeting EV may improve outcomes in
rapamycin treated patients.
To test this hypothesis we will determine: Aim 1. The effect of EV-cargo on CSC plasticity and survival of LAM
cells; Aim 2. Impact of EV-cargo on lung remodeling and lung seeding by LAM cells; and Aim 3. The effect of
inhibitors of EV uptake or EV biogenesis, individually or in combination with rapamycin, on lung remodeling
and LAM metastasis in vivo.
Our approaches include: the culture systems to test impact of EV-cargo on circulating LAM cells, novel LAM
mouse models in conjunction with longitudinal non-invasive live imaging, and studies with patient samples to
corroborate in vitro and mouse data and establish EV cargo as biomarker of LAM progression.
This project will impact the filed by establishing EV is a new therapeutic target for LAM and providing
foundation for repurposing approved EV-targeting drugs for LAM.
