23P Identification of HPSE as potential novel therapeutic target for lung adenocarcinoma patients

Lung cancer is a leading cause of mortality globally, particularly the subtype called lung adenocarcinoma (LUAD). Current treatments have limited success, emphasizing the need for better therapies. Heparan sulfate proteoglycans (HSPGs) and heparanase (Hpse) play important roles in cancer progression, including LUAD, but their exact functions are not fully understood. Our study aims to explore Hpse's relevance in LUAD progression and its effects on tumor cells. We introduced shRNAs by lentiviral transfections against heparanase into a murine and a human cell line. We performed intravenous and orthotopic injections to assess the effects of our genetic perturbations on tumor growth, survival, and the tumor immune microenvironment. The study investigated the correlation between heparanase mRNA expression and overall survival in LUAD patients. Using the PRECOGG database and the Cancer Genome Atlas, we found that elevated HPSE expression correlated with poor overall survival in LUAD patients. Additionally, in vitro experiments demonstrated that heparanase promoted migration and invasion of lung cancer cells, suggesting its role in metastasis. Moreover, in vivo studies using mouse models showed that Hpse knockdown reduced tumor growth and metastasis and increased the survival of mice. Spectral flow cytometry analysis revealed many changes in the immune microenvironment between tumors with high and low Hpse expression, with significant alterations in myeloid and lymphoid cell populations. Notably, in Hpsel-low tumors, alveolar macrophages were more abundant. Surprisingly, these macrophages displayed an anti-tumorigenic phenotype characterized based on single-cell sequencing performed on leukocytes. To conclude, our findings support our clinical analysis revealing that heparanase should be investigated further as a therapeutic target for patients with LUAD. More effort should be put towards inhibitors and trials should focus on this patient population that is in dire need of novel treatment options.