Over 90% of pancreatic ductal adenocarcinomas (PDAC) express mesothelin (MSLN). Overexpression or knockdown of MSLN has been implicated in PDAC aggressiveness. This activity has been ascribed to MSLN-induced activation of MAPK or NF-κB signaling pathways and to interaction of MSLN with its only known binding partner, MUC16. Here, we used CRISPR/Cas9 gene editing to delete MSLN from PDAC, then restored expression of wild-type (WT) or Y318A mutant MSLN by viral transduction. We found that MSLN KO cells grew in culture and as subcutaneous tumors in mouse xenografts at the same rate as WT cells but formed intraperitoneal metastases poorly. Complementation with WT MSLN restored intraperitoneal growth, whereas complementation with Y318A mutant MSLN, which does not bind MUC16, was ineffective at enhancing growth in both MUC16(+) and MUC16(−) models. Restoration of WT MSLN did enhance growth but did not affect cell-to-cell binding, cell viability in suspension or signaling pathways previously identified as contributing to the protumorigenic effect of MSLN. RNA deep sequencing of tumor cells identified no changes in transcriptional profile that could explain the observed phenotype. Furthermore, no histologic changes in tumor cell proliferation or morphology were observed in mature tumors. Examination of nascent MSLN KO tumors revealed decreased microvascular density as intraperitoneal tumors were forming, followed by decreased proliferation, which resolved by 2 weeks postimplantation. These data support a model whereby MSLN expression by tumor cells contributes to metastatic colonization. Implications: MSLN confers a growth advantage to tumor cells during colonization of peritoneal metastasis. Therapeutic blockade of MSLN might limit peritoneal spread.

Perivascular adipose tissue (PVAT) is a special deposit of fat tissue surrounding the vasculature. Previous studies suggest that PVAT modulates the vasculature function in physiological conditions and is implicated in the pathogenesis of vascular diseases. Understanding how PVAT influences vasculature function and vascular disease progression is important. Extracellular vesicles (EVs) are novel mediators of intercellular communication. EVs encapsulate molecular cargo such as proteins, lipids, and nucleic acids. EVs can influence cellular functions by transferring the carried bioactive molecules. Emerging evidence indicates that PVAT-derived EVs play an important role in vascular functions under health and disease conditions. This review will focus on the roles of PVAT and PVAT-EVs in obesity, diabetic, and metabolic syndrome-related vascular diseases, offering novel insights into therapeutic targets for vascular diseases.

Vascular cognitive impairment and dementia (VCID) encompass a spectrum of cognitive syndromes ranging from mild cognitive impairment to vascular dementia, accounting for approximately 15–20% of all dementia cases and representing the second most common form of dementia. Despite its high prevalence and clinical burden, effective therapeutic strategies remain lacking. Increasing evidence indicates that vascular dysfunction plays a central role in the pathogenesis of VCID by compromising cerebrovascular integrity, impairing endothelial function, and disrupting neurovascular coupling, which collectively contribute to cognitive decline. Stem cells have emerged as promising candidates for promoting vascular repair and neurovascular coupling. Notably, extracellular vesicles (EVs) derived from stem cells exert reparative and protective effects by transferring bioactive molecules that enhance endothelial function and preserve the blood–brain barrier (BBB) function to affected regions. This review summarizes the current knowledge of VCID from a vascular perspective, highlights recent advances in understanding stem cells and their derived EVs in promoting vascular repair and alleviating cognitive decline, and discusses future directions for translating these insights into innovative therapeutic strategies for VCID.

In vivo BLI of mice inoculated IP with Luc/GFP+ KLM1 Mock or KO#2 on day 3 (D3), 7 (D7) and 14 (D14) post-injection.

Examination of involvement of NF-κB pathway in MSLN IP pro-tumorigenicity.

Identifying a novel mediator for MSLN activity using qPCR.