Huanhuan He

PLIN2 Promotes Lipid Accumulation in Ascites‐Associated Macrophages and Ovarian Cancer Progression by HIF1α/SPP1 Signaling

AbstractA major characteristic of ovarian cancer (OC) is its unique route of metastasis via ascites. The immune microenvironment in ascites remains understudied, leaving the mechanism of ascites‐mediated abdominal metastasis obscure. Here, a single‐cell transcriptomic landscape of CD45+ immune cells across multiple anatomical sites is depicted, including primary tumors, metastatic lesions, and ascites, from patients diagnosed with high‐grade serous ovarian carcinoma (HGSOC). A novel subset of perilipin 2 high (PLIN2hi) macrophages are identified that are enriched in ascites and positively correlated with OC progression, hence being designated as “ascites‐associated macrophages (AAMs)”. AAMs are lipid‐loaded with overexpression of the lipid droplet protein PLIN2. Overexpression or suppression of PLIN2 can enhance or inhibit tumor cell migration, invasion, and vascular permeability in vitro, which is also confirmed in vivo. Mechanistically, it is demonstrated that PLIN2 boosts HIF1α/SPP1 signaling in macrophages, thereby exerting pro‐tumor functions. Finally, a PLIN2‐targeting liposome is designed to efficiently suppress ascites production and tumor metastasis. Taken together, this work provides a comprehensive characterization of the cancer‐promoting function and lipid‐rich property of ascites‐enriched PLIN2hi macrophages, establishes a link between lipid metabolism and hypoxia within the context of the ascites microenvironment, and elucidates the pivotal role of ascites in trans‐coelomic metastasis of OC.

Macrophage-mediated vascular permeability via VLA4/VCAM1 pathway dictates ascites development in ovarian cancer

The development of ascites correlates with advanced stage disease and poor prognosis in ovarian cancer. Vascular permeability is the key pathophysiological change involved in ascites development. Previously, we provided evidence that perivascular M2-like macrophages protect the vascular barrier through direct contact with endothelial cells (ECs). Here, we investigated the molecular mechanism and its clinical significance in the ovarian cancer setting. We found that upon direct coculture with the endothelium, M2 macrophages tuned down their VLA4 and reduced the levels of VCAM1 in ECs. On the other hand, ectopically overexpressing VLA4 in macrophages or VCAM1 in ECs induced hyperpermeability. Mechanistically, downregulation of VLA4 or VCAM1 led to reduced levels of RAC1 and ROS, which resulted in decreased phosphorylation of PYK2 (p-PYK2) and VE-cadherin (p-VE-cad), hence enhancing cell adhesion. Furthermore, targeting the VLA4/VCAM1 axis augmented vascular integrity and abrogated ascites formation in vivo. Finally, VLA4 expression on the macrophages isolated from ascites dictated permeability ex vivo. Importantly, VLA4 antibody acted synergistically with bevacizumab to further enhance the vascular barrier. Taking these data together, we reveal here that M2 macrophages regulate the vascular barrier though the VCAM1/RAC1/ROS/p-PYK2/p-VE-cad cascade, which provides specific therapeutic targets for the treatment of malignant ascites.