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 O. Oladipo, Matthew T. Taylor, Brenda Umenita Imo, Emily Ma, Jaya Manjunath, Alexander Kollhoff, June Deng, Varsha Parthasarathy, Karen Cravero, Melika Marani, Mindy D 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
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.