Extracellular Matrix and Fibroblast Activation in Lymphangioleiomyomatosis.

Area of Science:

• Cell Biology
• Molecular Medicine
• Rare Diseases

Background:

• Lymphangioleiomyomatosis (LAM) is a rare lung disease driven by mTORC1 pathway hyperactivation.
• LAM cells exhibit cancer stem cell (CSC) characteristics and express extracellular matrix (ECM) genes.
• The ECM may shield LAM lesions from immune surveillance.

Purpose of the Study:

• To investigate the role of ECM gene expression in LAM.
• To evaluate the efficacy of novel mTORC1 inhibitors in LAM models.
• To understand the translational control mechanisms of ECM production in LAM.

Main Methods:

• Single-cell RNA sequencing (scRNA-seq) to classify LAM cell states.
• Treatment of LAM-associated fibroblasts (LAFs) with RMC-5552 and rapamycin.
• Analysis of collagen gene expression and mTORC1 substrate phosphorylation.

Main Results:

• LAM cells with high and intermediate CSC-like states express significant ECM genes, including collagens and CTHRC1.
• RMC-5552 inhibited translation of COL1A1 and COL6A1, and phosphorylation of S6K1/S6 and 4E-BP1/eIF4E.
• Rapamycin only inhibited S6K1/S6, while C82 inhibited collagen transcription but not pS6 or p4E-BP1.

Conclusions:

• mTORC1-driven, rapamycin-insensitive 4E-BP1/eIF4E translational control is critical for ECM gene expression in LAM.
• RMC-5552's inhibition of ECM production and fibroblast activation may lead to LAM cell destruction.
• RMC-5552 offers a potential new therapeutic strategy for more enduring LAM treatment.