Endothelial cell-specific LAT1 ablation normalizes tumor vasculature.

Area of Science:

• Oncology
• Vascular Biology
• Molecular Biology

Background:

• Tumor vasculature exhibits unique characteristics, including the expression of system L amino acid transporter LAT1 on some endothelial cells.
• LAT1 plays a role in amino acid transport, potentially influencing tumor microenvironment and metastasis.

Purpose of the Study:

• To investigate the role of LAT1 in tumor endothelial cells.
• To determine the therapeutic potential of targeting LAT1 in cancer.

Main Methods:

• Generated endothelial cell-specific LAT1 conditional knockout mice (Slc7a5flox/flox; Cdh5-Cre-ERT2).
• Administered LAT1 inhibitor (nanvuranlat) and induced tryptophan deprivation in cell culture and animal models.
• Analyzed tumor vasculature morphology, metastasis, inflammatory markers (VCAM1, E-selectin), and intracellular signaling pathways (MEK/ERK).

Main Results:

• Conditional knockout of LAT1 in endothelial cells normalized tumor vasculature shape and reduced lung metastasis.
• LAT1 inhibition and tryptophan deprivation decreased VCAM1 and E-selectin expression on HUVECs, reducing monocyte attachment.
• Tryptophan deprivation activated the MEK1/2-ERK1/2 pathway, leading to cystathionine γ lyase (CTH) induction.
• CTH-mediated hydrogen sulfide (H2S) production contributed to vascular normalization and enhanced chemotherapeutic delivery.

Conclusions:

• LAT1 is a critical regulator of tumor endothelial cell function and metastasis.
• Targeting LAT1 with inhibitors or substrate deprivation offers a therapeutic strategy for cancer treatment.
• The mechanism involves H2S production, leading to vascular normalization and improved drug delivery to tumors.