Valyi-Nagy, T. | bioRxiv Science

bioRxiv2022

Impaired Barrier Integrity of the Skeletal Muscle Vascular Endothelium Drives Progression of Cancer Cachexia

Cancer patients experience cachexia, which is characterized by extensive skeletal muscle wasting that worsens the quality of life and increases mortality. Currently, there are no approved treatments that can effectively counteract cancer cachexia. Vascular endothelial cells (ECs) are essential for maintaining tissue perfusion, nutrient supply, and preventing inappropriate transmigration of immune cells into the tissue. However, little is known about the role of the muscle vasculature in cancer cachexia. We hypothesized that endothelial dysfunction in the skeletal muscle mediates cancer cachexia. Using transgenic pancreatic ductal adenocarcinoma (PDAC) mice and a tissue clearing and high-resolution 3D-tissue imaging approach, we found that the loss of skeletal muscle vascular density precedes the loss of muscle mass. Importantly, we show that cancer cachexia patients exhibit significantly decreased muscle vascular density and severe muscle atrophy when compared to non-cancer patients. Unbiased single cell transcriptomic analyses of the muscle endothelium unveiled a unique EC population present in cachexia muscles. Increased circulating Activin-A suppresses the expression of the transcriptional co-activator PGC1 in the muscle endothelium, thus disrupting junctional integrity in the vasculature and increasing vascular leakage. Conversely, restoration of endothelial-specific PGC1 prevented the decreased vascular density and muscle loss observed in tumor-bearing mice. Our study suggests that EC-PGC1 is essential for maintaining the integrity of the skeletal muscle vascular barrier and that restoring muscle endothelial function could be a valuable therapeutic approach to prevent or reverse cancer cachexia.

cancer biology↗

bioRxiv2018

Transcriptional Profiling of Patient Isolates Identifies a Novel TOR Regulatory Pathway in Cryptococcal Virulence

Human infection with Cryptococcus causes up to a quarter million AIDS-related deaths annually and is the most common cause of non-viral meningitis in the United States. As an opportunistic fungal pathogen, C. neoformans is distinguished by its ability to adapt to diverse host environments including plants, amoeba and mammals. In the present study, comparative transcriptomics of the fungus within human cerebrospinal fluid identified expression profiles representative of low-nutrient adaptive responses. Transcriptomics of fungal isolates from a cohort of HIV/AIDS patients identified a low nutrient-induced gene, an alternative carbon nutrient transporter STL1 associated with poor early fungicidal activity, an important clinical prognostic marker. Mouse modeling and pathway analysis demonstrated a role for STL1 in mammalian pathogenesis and revealed that STL1 expression is regulated by a novel target-of-rapamycin (TOR)-related multi-gene regulatory mechanism involving the CAC2 subunit of the chromatin assembly complex 1, CAF-1. In this pathway, the TOR-related RNA chaperone, VAD1 was found to transcriptionally regulate a cryptococcal homolog of a cytosolic protein Ecm15, in turn, required for nuclear transport of the Cac2 protein. Derepression of STL1 by the CAC2-containing CAF-1 complex was mediated by Cac2 and modulated binding and suppression of the STL1 enhancer element. Derepression of STL1 resulted in enhanced survival and growth of the fungus in the presence of low nutrient, alternative carbon sources, facilitating virulence in mice. The study underscores the utility of ex vivo expression profiling of fungal clinical isolates and provides fundamental genetic understanding of saprophyte adaption to the human host.\n\nAuthor summaryThe fungus Cryptococcus is a fungal pathogen that kills an estimated quarter of a million individuals yearly and is the most common cause of meningitis in the United States. The fungus is carried in about 10% of the adult population and, after re-activation, causes disease in a wide variety of individuals including HIV-infected as well as immunosuppression either from genetic defects or after immune suppressive treatments due to transplant conditioning, cancer therapy or treatment of autoimmune diseases. The fungus is widely carried in the soil and trees and can infect plants, single cell organisms and even dolphins. However, mechanisms for this widespread ability to infect a variety of hosts are poorly understood. The present study identified adaptation to low nutrients as a key property that allows the fungus to infect these diverse hosts and identified a nutrient transporter, STL1 to be associated with a marker of poor clinical outcome in a cohort of HIV/AIDS patients. Understanding molecular mechanisms involved in environmental adaptation may help to design better methods of control and treatment of widely dispersed fungal pathogens such as Cryptococcus.

microbiology↗