Single-cell multiomic analysis identifies a HOX-PBX gene network regulating the survival of lymphangioleiomyomatosis cells.

Autor:	Olatoke T; Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, University of Cincinnati, Cincinnati, OH 45267, USA., Wagner A; Division of Pulmonary Biology, Perinatal Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA., Astrinidis A; Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, University of Cincinnati, Cincinnati, OH 45267, USA., Zhang EY; Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, University of Cincinnati, Cincinnati, OH 45267, USA., Guo M; Division of Pulmonary Biology, Perinatal Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA., Zhang AG; Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, University of Cincinnati, Cincinnati, OH 45267, USA., Mattam U; Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, University of Cincinnati, Cincinnati, OH 45267, USA., Kopras EJ; Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, University of Cincinnati, Cincinnati, OH 45267, USA., Gupta N; Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, University of Cincinnati, Cincinnati, OH 45267, USA., Smith EP; Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, University of Cincinnati, Cincinnati, OH 45267, USA., Karbowniczek M; Department of Immunotherapeutics and Biotechnology, Jerry H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center, Abilene, TX 79601, USA., Markiewski MM; Department of Immunotherapeutics and Biotechnology, Jerry H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center, Abilene, TX 79601, USA., Wikenheiser-Brokamp KA; Division of Pathology and Laboratory Medicine, Perinatal Institute, Division of Pulmonary Biology, Division of Pulmonary Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.; Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA., Whitsett JA; Division of Pulmonary Biology, Perinatal Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA., McCormack FX; Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, University of Cincinnati, Cincinnati, OH 45267, USA., Xu Y; Division of Pulmonary Biology, Perinatal Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.; Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA., Yu JJ; Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, University of Cincinnati, Cincinnati, OH 45267, USA.
Jazyk:	angličtina
Zdroj:	Science advances [Sci Adv] 2023 May 10; Vol. 9 (19), pp. eadf8549. Date of Electronic Publication: 2023 May 10.
DOI:	10.1126/sciadv.adf8549
Abstrakt:	Lymphangioleiomyomatosis (LAM) is a rare, progressive lung disease that predominantly affects women. LAM cells carry TSC1/TSC2 mutations, causing mTORC1 hyperactivation and uncontrolled cell growth. mTORC1 inhibitors stabilize lung function; however, sustained efficacy requires long-term administration, and some patients fail to tolerate or respond to therapy. Although the genetic basis of LAM is known, mechanisms underlying LAM pathogenesis remain elusive. We integrated single-cell RNA sequencing and single-nuclei ATAC-seq of LAM lungs to construct a gene regulatory network controlling the transcriptional program of LAM cells. We identified activation of uterine-specific HOX-PBX transcriptional programs in pulmonary LAM CORE cells as regulators of cell survival depending upon HOXD11-PBX1 dimerization. Accordingly, blockage of HOXD11-PBX1 dimerization by HXR9 suppressed LAM cell survival in vitro and in vivo. PBX1 regulated STAT1/3, increased the expression of antiapoptotic genes, and promoted LAM cell survival in vitro. The HOX-PBX gene network provides promising targets for treatment of LAM/TSC mTORC1-hyperactive cancers.
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu