Role of the extracellular matrix (ECM) homeostasis in HPV infection and persistence.

• Grant number: 24/23508-4
• Support Opportunities: Scholarships abroad - Research
• Start date: October 15, 2025
• End date: October 14, 2026
• Field of knowledge: Biological Sciences - Microbiology - Biology and Physiology of Microorganisms
• Principal Investigator: Enrique Mario Boccardo Pierulivo
• Grantee: Enrique Mario Boccardo Pierulivo
• Host Investigator: John Doorbar
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Institution abroad: University of Cambridge, England

Abstract

High oncogenic risk Human papillomaviruses (HPVs), such as HPV16 and HPV18, cause the totality of cervical cancers in women, and a relevant fraction of anogenital and head and neck tumors in all genders, accounting for almost 4,5% of all human cancers. Besides, low oncogenic-risk types, such as HPV6 and HPV11, are responsible for over 30 million of genital warts cases every year. The establishment and progression of productive infections and tumors caused by these agents involves a series of events that modulate the interaction of the host cell with other cellular components of the tissue and the extracellular matrix (ECM). Up regulation of metalloproteinases types 2 and 9 (MMP-2 and MMP-9) expression and activity are the most common ECM modifications in precursor cervical lesions and invasive carcinoma. We reported that this event correlated with the down-regulation of MMP inhibitors, including the REversion-inducing Cysteine-rich protein with Kazal motifs (RECK). Besides, we showed that RECK suppression is related to the expression of HPV early proteins in vitro, is an early event in the natural history of HPV-related cancers and correlates with disease prognosis. However, little is known about the interplay of HPV early proteins and RECK during initial infection, persistence, lesion establishment and progression. This is an important issue to address since RECK can inhibit cellular stemness which affect virus persistence. Conversely, RECK can be targeted by direct and indirect virus-mediated mechanisms associated to immune evasion. The study of these events using innovative cell culture approaches and single cell gene expression analysis is fundamental to determine the role of ECM alterations on the fate of HPV infection.