# APOA2-mediated endothelial mesenchymal transition and cancer lipid metabolism reprogramming confers antiangiogenic drug resistance through TGF-β

## TL;DR

This study shows how a protein called APOA2 helps liver cancer resist antiangiogenic drugs by changing cancer cell metabolism and reducing drug targets.

## Contribution

The study identifies APOA2 as a novel mediator of antiangiogenic drug resistance in hepatocellular carcinoma through TGF-β-driven mechanisms.

## Key findings

- APOA2 overexpression in HCC leads to resistance to antiangiogenic drugs by downregulating VEGFR2 and promoting cancer cell proliferation.
- APOA2 induces TGF-β secretion, which reprograms lipid metabolism and promotes fatty acid oxidation in cancer cells.
- Blocking TGF-β function eliminates APOA2-mediated resistance and reduces tumor angiogenesis and proliferation.

## Abstract

Angiogenesis is a hallmark of hepatocellular carcinoma (HCC), yet most cases resist antiangiogenic drugs (AADs) targeting VEGFA-VEGFR2, and the molecular mechanisms remain largely unknown. Here, we show that apolipoprotein A2 (APOA2) mediates endothelial-to-mesenchymal transition and reprograms cancer lipid metabolism, inducing AAD resistance in HCC. This occurs via downregulating VEGFR2 in vascular endothelial cells and promoting high cancer cell proliferation with low apoptosis. The whole transcriptome sequencing of unresectable human HCC specimens revealed elevated expression of APOA2 in the AAD-resistant group. Furthermore, the overexpression of APOA2 confirmed resistance to AAD therapy in an HCC-bearing mouse model. AAD treatment had no effect on tumor angiogenesis in HCC overexpressing APOA2, while cancer cells exhibited increased proliferation and reduced apoptosis. Mechanistically, proteomic analysis verified that APOA2 significantly upregulates transforming growth factor-beta (TGF-β) related proteins. Furthermore, the secretion of TGF-β was markedly increased in HCC cell culture medium and the blood of HCC-bearing mice after APOA2 overexpression. On the one hand, TGF-β reduced VEGFR-2 expression and increased mesenchymal gene expression in ECs. On the other hand, TGF-β initiated fatty acid (FA) oxidation metabolic reprogramming and increased uptake of free FAs, stimulating cancer cell proliferation. Furthermore, inhibition of TGF-β eliminated APOA2-mediated EndoMT and cancer lipid metabolism reprogramming. Notably, HCC with high expression of APOA2 relied on TGF-β to promote cell proliferation and angiogenesis, and pharmacological loss of TGF-β function can reduce angiogenesis and malignant tumor proliferation. These findings reveal an effective cancer therapy concept by inhibition of TGF-β, targeting angiogenesis and lipid metabolism reprogramming.