Single-Cell RNA Sequencing Reveals Dysregulated POSTN+WNT5A+ Fibroblast Subclusters in Prurigo Nodularis

Jay R Patel; Marina Z Joel; Kevin K Lee; Anusha Kambala; Hannah Cornman; Olusola Oladipo; Matthew Taylor; Brenda Umenita Imo; Emily Z Ma; Jaya Manjunath; Alexander L Kollhoff; June Deng; Varsha Parthasarathy; Karen Cravero; Melika Marani; Mindy Szeto; Ryan Zhao; Sreenidhi Sankararaman; Ruixiang Li; Shanae Henry; Thomas Pritchard; Vito Rebecca; Madan M Kwatra; Won Jin Ho; Xinzhong Dong; Sewon Kang; Shawn G Kwatra

doi:10.1016/j.jid.2023.12.021

Single-Cell RNA Sequencing Reveals Dysregulated POSTN+WNT5A+ Fibroblast Subclusters in Prurigo Nodularis

J Invest Dermatol. 2024 Jan 20:S0022-202X(24)00021-6. doi: 10.1016/j.jid.2023.12.021. Online ahead of print.

Authors

Jay R Patel¹, Marina Z Joel¹, Kevin K Lee¹, Anusha Kambala¹, Hannah Cornman¹, Olusola Oladipo¹, Matthew Taylor¹, Brenda Umenita Imo¹, Emily Z Ma¹, Jaya Manjunath¹, Alexander L Kollhoff¹, June Deng¹, Varsha Parthasarathy¹, Karen Cravero¹, Melika Marani¹, Mindy Szeto¹, Ryan Zhao¹, Sreenidhi Sankararaman¹, Ruixiang Li¹, Shanae Henry¹, Thomas Pritchard¹, Vito Rebecca², Madan M Kwatra³, Won Jin Ho⁴, Xinzhong Dong⁵, Sewon Kang¹, Shawn G Kwatra⁶

Affiliations

¹ Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
² Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA.
³ Department of Anesthesiology, Duke University School of Medicine, Durham, North Carolina, USA; Department of Pharmacology & Cancer Biology, Duke University School of Medicine, Durham, North Carolina, USA.
⁴ The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA; Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
⁵ The Solomon H. Snyder Department of Neuroscience, Center for Sensory Biology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA; Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
⁶ Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. Electronic address: skwatra1@jhmi.edu.

PMID: 38246584
DOI: 10.1016/j.jid.2023.12.021

Abstract

Prurigo nodularis (PN) is an intensely pruritic, inflammatory skin disease with a poorly understood pathogenesis. We performed single-cell transcriptomic profiling of 28,695 lesional and nonlesional PN cells. Lesional PN has increased dysregulated fibroblasts (FBs) and myofibroblasts. FBs in lesional PN were shifted toward a cancer-associated FB-like phenotype, with POSTN+WNT5A+ cancer-associated FBs increased in PN and similarly so in squamous cell carcinoma. A multicenter cohort study revealed an increased risk of squamous cell carcinoma and cancer-associated FB-associated malignancies (breast and colorectal) in patients with PN. Systemic fibroproliferative diseases (renal sclerosis and idiopathic pulmonary fibrosis) were upregulated in patients with PN. Ligand-receptor analyses demonstrated an FB neuronal axis with FB-derived WNT5A and periostin interactions with neuronal receptors melanoma cell adhesion molecule and ITGAV. These findings identify a pathogenic and targetable POSTN+WNT5A+ FB subpopulation that may predispose cancer-associated FB-associated malignancies in patients with PN.

Keywords: Fibroblasts; Periostin; Prurigo nodularis; WNT5A; scRNAseq.