Endothelial cells (ECs) have a central role in promoting metastasis, the leading cause of death for patients with cancer. Yet, while the interplay between cancer cells and endothelial cells at the primary tumor site has been extensively studied, the types of molecular interactions that occur when disseminated cancer cells encounter quiescent ECs at the premetastatic niche (PMN) are less well understood.
Tumor necrosis factor (TNF)–related apoptosis-inducing ligand (TRAIL), encoded by the gene TNF superfamily member 10 (TNFSF10), is known to trigger apoptosis in tumor cells by binding to its cognate death receptors. As such, TRAIL receptor agonists are being developed as cancer therapies. However, the limited efficacy of these agents in clinical trials suggests that tumor cells can resist TRAIL-induced apoptosis, highlighting the need for deeper investigation of the endogenous TRAIL system.
Recently, researchers at the Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, VIB, Leuven, showed that endothelial cells in the PMN express high levels of TRAIL that impede early metastasis colonization via a mechanism independent of death receptor-binding. Their data, published in Science Advances, include the finding that lung metastases resulting from EC-specific deletion of TRAIL in an experimental mouse model can be rescued with EC-targeting lipid nanoparticles (LNPs) containing tnfsf10 mRNA, which represents a potential new means of treating cancer.
TRAIL expression in ECs maintains the integrity of the vascular barrier
To investigate the physiological role of TRAIL in ECs, Riera-Domingo et al. used short hairpin RNAs (shRNAs) to silence TRAIL in human vascular endothelial cells (HUVECs) before measuring trans-endothelial electrical resistance (TEER) as an indicator of vascular tightness. TEER decreased significantly in the shTRAIL samples compared to a scrambled control, suggesting that TRAIL is required to form a tight, intact, and confluent vascular layer. EC-specific deletion of TRAIL in a novel murine strain led to fibronectin entering the lung parenchyma from the serum, providing further evidence that TRAIL expression in quiescent ECs is necessary to preserve the integrity of the vascular barrier.
Endogenous TRAIL curbs early metastasis colonization independently of DR5 expression
By orthotopically injecting TRAIL wild-type (Trail+/+) and TRAIL knockout (Trail-/-) mice with 4T1 or EMT6.5 cells, two highly metastatic triple-negative breast cancer models, Riera-Domingo et al. demonstrated that TRAIL deletion dramatically increased the number of spontaneous lung metastases. Similar results were observed when mice were injected with 4T1-DR5 KO cancer cells, indicating TRAIL to have an anti-metastatic effect that is independent of DR5 expression. When 4T1 or 4T1-DR5 KO cells were injected into the bloodstream of animals lacking TRAIL expression, the lung cancer cell burden was increased after just 24 hours, revealing TRAIL to be important in preventing early metastatic organ colonization.
Targeted LNP delivery rescues EC-specific TRAIL deletion
Nucleoside-modified (m1Ψ-5′-triphosphate) tnfsf10 mRNAs were produced to contain 101 nucleotide-long poly(A) tails and were co-transcriptionally capped using TriLink’s CleanCap® trinucleotide cap1 analog.The mRNAs were then encapsulated in LNPs, which were targeted to endothelial cells through conjugation to antibodies for murine CD31/platelet endothelial cell adhesion molecule 1 (PECAM1). When the mRNA-loaded LNPs were delivered to mice in which TRAIL had been deleted in ECs, the increase in experimental lung metastases induced by the EC-specific deletion was rescued. Translating these effects into human patients represents a potential strategy to address cancer metastasis and improve survival outcomes.
Article reference: Riera-Domingo C, Leite-Gomes E, Charatsidou I, et al. Breast tumors interfere with endothelial TRAIL at the premetastatic niche to promote cancer cell seeding. Science Advances 2023; Vol. 9, No. 12