ATP6L impairs vascular stability in colorectal cancer via PDGFB/PDGFRβ signaling

Vascular instability, characterized by impaired pericyte coverage, is a hallmark of tumor progression. ATP6L is highly expressed in colorectal cancer (CRC) tissues and promotes tumor progression by enhancing the tumor microvasculature; however, its direct impact on vascular stability remains unclear. ATP6L expression, microvascular morphology, and pericyte coverage were analyzed by immunohistochemistry in a cohort of 179 CRC specimens, and the role of ATP6L in vascular stability was further investigated by modulating its expression both in vitro and in vivo. In vitro, MC38 and CT26 cells with ATP6L overexpression or knockdown were co-cultured with mouse vascular smooth muscle cells (MOVAS), and MOVAS proliferation, migration, and apoptosis were evaluated using EdU incorporation, transwell migration, and TUNEL staining assays, respectively. PDGFB secretion and PDGFRβ expression were assessed by ELISA, Western blotting, and immunofluorescence. Along the normal colorectal mucosa-adenoma-adenocarcinoma sequence, ATP6L upregulation was closely associated with progressive vascular instability, characterized by loss of pericyte coverage and increasing vascular morphological heterogeneity. Mechanistically, ATP6L overexpression promoted extracellular acidification, suppressed PDGFB secretion, and subsequently reduced PDGFRβ expression in pericytes, thereby impairing their recruitment and survival. Conversely, ATP6L knockdown attenuated extracellular acidification, restored PDGFB/PDGFRβ signaling, and rescued pericyte proliferation, migration, and survival. These findings identify ATP6L as a key mediator of perivascular dysfunction in CRC and demonstrate that ATP6L-induced extracellular acidification disrupts vascular stability by suppressing the PDGFB/PDGFRβ signaling axis and impairing pericyte function.