Abstract 3335: Trop-1/EpCAM Thr115 is a novel inducer of cancer cell proliferation and drives hyperproliferative lung damage in COVID-19

Abstract SARS-CoV-2 infection triggers an acute reaction that can severely impair lung function. However, the underlying molecular processes are poorly understood. Our findings showed that the pM115T polymorphism of TROP1/EPCAM associates with COVID-19 severity. The p.M115T polymorphism of TROP1/EPCAM gene had been associated with higher frequency of early-onset breast cancer. However, the functional role of Thr115 Trop-1/EpCAM remained essentially unknown. We explored whether the Thr115 Trop-1/EpCAM acts as a driver of cell proliferation and whether this can play a role in lung pathology / lesion repair in COVID-19 patients. TROP1/EPCAM knockout embryonic stem cells showed altered proliferation. The Trop-1/EpCAM Thr115 allele was found to drive hyperproliferative capacity in murine fibrosarcoma cells, whereas the Met115 allele did not. A corresponding role was assessed in human colon cancer cells, through CRISPR-Cas9 ablation of the endogenous TROP1/EPCAM and comparative transfection of Trop-1/EpCAM Thr115 or Met115 alleles. The Trop-1/EpCAM Thr115 was shown to induce colon cancer cell hyperproliferation, whereas the Met115 allele was devoid of cell growth-driving capacity. Trop-1/EpCAM Thr115 was correspondingly shown to drive the main pathological mechanisms that lead to oxygen-exchange impairment in COVID-19. Morphometric analysis of autoptic lung samples, immunohistochemistry analysis for Trop-1/EpCAM expression, Ki67 proliferation index and comparative computational image analysis were utilized to analyze SARS-CoV-2-infected lungs at autopsy. This showed hyperproliferation of Thr115 Trop-1/EpCAM+ epithelial cells over the alveolar epithelium damaged by the infection. This correlated with Thr115 Trop-1/EpCAM+ inflammatory cells hyperproliferation and alveolar hyaline membrane formation. These multi-layered barriers were computed to reduce oxygen diffusion by up to 100-fold versus normal alveolar structures, with a critical pathological impact. Our findings identify a novel mechanism of induction of cancer cell proliferation by a polymorphic, wild-type Trop-1/EpCAM. A corresponding process was shown to operate in COVID-19 patients, causing an aberrant lung repair, via Trop-1/EpCAM Thr115-induced cell overproliferation. These findings indicate unexpected parallels between inflammation-driven wound-repair in the lungs and cancer cell hyperproliferation as driven by via Trop-1/EpCAM Thr115. Novel diagnostic/ prognostic/ therapeutic opportunities are suggested in Thr115 Trop-1/EpCAM+ COVID-19 patients, and in Thr115 Trop-1/EpCAM+ cancer patients. Acknowledgments: Grant PNRR - Tuscany Health Ecosystem (THE), Next Generation EU, Missione 4, Componente 2, Inv. 1.5, CUP B63C22000680007. Citation Format: Saverio Alberti, Milena Baldassarri, Marco Trerotola, Giulia Brunelli, Laura Bergantini, Giulia Benedetta tella, Rollo, Emanuela Guerra, Ludovica martina ceci, Pantalone, Elena Bargagli, Rossano Lattanzio, Antonino Moschella, Federica M. Previtera, Cristiana Bellan, Nicola La Francesca, Cristoforo Pomara, Network for Italian Genomes, GEN-COVID Multicenter Study, Alessandra Renieri, Chiara Fallerini. Trop-1/EpCAM Thr115 is a novel inducer of cancer cell proliferation and drives hyperproliferative lung damage in COVID-19 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3335.