Tear fluid as noninvasive liquid biopsy reveals proteins associated with malignant transformation of oral lesions

Erison Santana dos Santos; Daniela C. Granato; Carolina Moretto Carnielli; Ariane F. B. Lopes; Daniella de Figueiredo; Luciana Daniele Trino; Fábio Malta de Sá Patroni; Bianca Alves Pauletti; Romênia R. Domingues; JAMILE DE OLIVEIRA SÁ; Tatiane M. Rossi; Ana Gabriela Costa Normando; Narmeen Daher; Nataly Kravchenko‐Balasha; Paul Debasis; Rosane Minghim; Luiz P. Kowalski; Alan Roger Santos‐Silva; Márcio Ajudarte Lopes; Thaís Bianca Brandão; Ana Carolina Prado Ribeiro; Adriana Franco Paes Leme

doi:10.1101/2025.11.06.686738

BiochemistrybioRxivNov 6, 2025

Preprint

Tear fluid as noninvasive liquid biopsy reveals proteins associated with malignant transformation of oral lesions

Erison Santana dos Santos iD, Daniela C. Granato iD, Carolina Moretto Carnielli iD, Ariane F. B. Lopes, Daniella de Figueiredo iD, Luciana Daniele Trino iD, Fábio Malta de Sá Patroni iD, Bianca Alves Pauletti iD, Romênia R. Domingues iD, JAMILE DE OLIVEIRA SÁ iD, Tatiane M. Rossi, Ana Gabriela Costa Normando iD, Narmeen Daher, Nataly Kravchenko‐Balasha iD, Paul Debasis, Rosane Minghim iD, Luiz P. Kowalski, Alan Roger Santos‐Silva iD, Márcio Ajudarte Lopes iD, Thaís Bianca Brandão iD, Ana Carolina Prado Ribeiro iD, Adriana Franco Paes Leme iD

Abstract

Oral leukoplakias (OLs) are premalignant lesions that can progress into oral squamous cell carcinoma (OSCC). This study hypothesized that tear fluid, as a noninvasive biofluid, reflects proteomic alterations associated with malignant transformation. The tear proteome of 44 individuals, including healthy controls, OL/PVL (proliferative verrucous leukoplakia), and OSCC patients, was deeply profiled, revealing 828 protein groups clustered according to histopathological alterations. N-glycoproteome analysis identified immune-related proteins, while public RNA-seq integration indicated immune imbalance marked by increased B-cell and decreased macrophage signatures during disease progression. Several immune-associated proteins and epithelial markers, including desmoplakin, KRT14, and DSC1, emerged as potential indicators of malignant transformation. These findings demonstrate that tear fluid reflects oral carcinogenic processes, thereby serving as a noninvasive liquid biopsy for early detection and clinical monitoring.

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