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

• Published in: Science advances Vol. 9; no. 19; p. eadf8549
• Main Authors: Olatoke, Tasnim, Wagner, Andrew, Astrinidis, Aristotelis, Zhang, Erik Y, Guo, Minzhe, Zhang, Alan G, Mattam, Ushodaya, Kopras, Elizabeth J, Gupta, Nishant, Smith, Eric P, Karbowniczek, Magdalena, Markiewski, Maciej M, Wikenheiser-Brokamp, Kathryn A, Whitsett, Jeffrey A, McCormack, Francis X, Xu, Yan, Yu, Jane J
• Format: Journal Article
• Language: English
• Published: United States American Association for the Advancement of Science 10-05-2023
• Subjects: Animals; Biomedicine and Life Sciences; Diseases and Disorders; Female; Gene Regulatory Networks; Homeodomain Proteins; Humans; Lung - metabolism; Lung - pathology; Lymphangioleiomyomatosis - metabolism; Lymphangioleiomyomatosis - pathology; Multiomics; Neoplasm Metastasis; Rats; SciAdv r-articles; Single-Cell Analysis; Transcription Factors - metabolism
• ISSN: 2375-2548; 2375-2548
• DOI: 10.1126/sciadv.adf8549

Lymphangioleiomyomatosis (LAM) is a rare, progressive lung disease that predominantly affects women. LAM cells carry
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
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.