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

Background

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.

Methods

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.

Results

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.

Conclusions

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.

Editorial acknowledgement

Clinical trial identification

Legal entity responsible for the study

The authors.

Funding

CIHR.

Disclosure

All authors have declared no conflicts of interest.