Konnie Guo

All Publications

• Repurposing an epithelial sodium channel inhibitor as a therapy for murine and human skin inflammation. Science translational medicine Winge, M. C., Nasrallah, M., Jackrazi, L. V., Guo, K. Q., Fuhriman, J. M., Szafran, R., Ramanathan, M., Gurevich, I., Nguyen, N. T., Siprashvili, Z., Inayathullah, M., Rajadas, J., Porter, D. F., Khavari, P. A., Butte, A. J., Marinkovich, M. P. 2024; 16 (777): eade5915

  Abstract

  Inflammatory skin disease is characterized by a pathologic interplay between skin cells and immunocytes and can result in disfiguring cutaneous lesions and systemic inflammation. Immunosuppression is commonly used to target the inflammatory component; however, these drugs are often expensive and associated with side effects. To identify previously unidentified targets, we carried out a nonbiased informatics screen to identify drug compounds with an inverse transcriptional signature to keratinocyte inflammatory signals. Using psoriasis, a prototypic inflammatory skin disease, as a model, we used pharmacologic, transcriptomic, and proteomic characterization to find that benzamil, the benzyl derivative of the US Food and Drug Administration-approved diuretic amiloride, effectively reversed keratinocyte-driven inflammatory signaling. Through three independent mouse models of skin inflammation (Rac1G12V transgenic mice, topical imiquimod, and human skin xenografts from patients with psoriasis), we found that benzamil disrupted pathogenic interactions between the small GTPase Rac1 and its adaptor NCK1. This reduced STAT3 and NF-κB signaling and downstream cytokine production in keratinocytes. Genetic knockdown of sodium channels or pharmacological inhibition by benzamil prevented excess Rac1-NCK1 binding and limited proinflammatory signaling pathway activation in patient-derived keratinocytes without systemic immunosuppression. Both systemic and topical applications of benzamil were efficacious, suggesting that it may be a potential therapeutic avenue for treating skin inflammation.

  View details for DOI 10.1126/scitranslmed.ade5915

  View details for PubMedID 39661704

• Advances in cutaneous squamous cell carcinoma. Nature reviews. Cancer Winge, M. C., Kellman, L. N., Guo, K., Tang, J. Y., Swetter, S. M., Aasi, S. Z., Sarin, K. Y., Chang, A. L., Khavari, P. A. 2023

  Abstract

  Human malignancies arise predominantly in tissues of epithelial origin, where the stepwise transformation from healthy epithelium to premalignant dysplasia to invasive neoplasia involves sequential dysregulation of biological networks that govern essential functions of epithelial homeostasis. Cutaneous squamous cell carcinoma (cSCC) is a prototype epithelial malignancy, often with a high tumour mutational burden. A plethora of risk genes, dominated by UV-induced sun damage, drive disease progression in conjunction with stromal interactions and local immunomodulation, enabling continuous tumour growth. Recent studies have identified subpopulations of SCC cells that specifically interact with the tumour microenvironment. These advances, along with increased knowledge of the impact of germline genetics and somatic mutations on cSCC development, have led to a greater appreciation of the complexity of skin cancer pathogenesis and have enabled progress in neoadjuvant immunotherapy, which has improved pathological complete response rates. Although measures for the prevention and therapeutic management of cSCC are associated with clinical benefit, the prognosis remains poor for advanced disease. Elucidating how the genetic mechanisms that drive cSCC interact with the tumour microenvironment is a current focus in efforts to understand, prevent and treat cSCC.

  View details for DOI 10.1038/s41568-023-00583-5

  View details for PubMedID 37286893

  View details for PubMedCentralID 4833641