TFEB triggers a matrix degradation and invasion program in triple-negative breast cancer cells upon mTORC1 repression

Area of Science:

• Oncology
• Molecular Biology
• Cell Biology

Background:

• The phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway is often overactive in triple-negative breast cancers (TNBCs), correlating with poor outcomes.
• This pathway is a key target for breast cancer therapies.

Purpose of the Study:

• To investigate the consequences of inhibiting mTOR-containing complex 1 (mTORC1) in triple-negative breast cancer models.
• To understand the molecular mechanisms underlying the response to mTORC1 inhibition.

Main Methods:

• Knockdown of key mTORC1 components and treatment with mTOR inhibitors in TNBC cell lines and patient-derived xenografts (PDXs).
• Analysis of extracellular matrix degradation, transcription factor EB (TFEB) nuclear translocation, endolysosome function, exocytosis, and cell phenotype.
• Assessment of invadopodia activity and tumor organization in xenograft models.

Main Results:

• mTORC1 repression led to a significant increase (approximately 10-fold) in extracellular matrix proteolytic degradation.
• Inhibition induced nuclear translocation of TFEB, activating genes involved in endolysosome function and exocytosis.
• This resulted in increased endolysosomal recycling, surface exposure of MT1-MMP, and enhanced invadopodia activity.
• A basal-like breast cancer cell phenotype and disrupted tumor organization were observed.

Conclusions:

• mTORC1 repression triggers pro-invasive mechanisms in TNBC, including enhanced matrix degradation and cell invasiveness.
• The findings necessitate a re-evaluation of the therapeutic strategy of using mTOR inhibitors in breast cancer treatment.
• Targeting the PI3K/AKT/mTOR pathway requires careful consideration of potential pro-tumorigenic effects in certain contexts.