Exploring how TAMs hijack the TRAIL system to fuel tumor progression and drug resistance

Metastasis is a complex multistep process whereby a subset of aggressive cancer cells exits the primary tumor and enter the blood circulation, which serves as a highway to travel systemically until they find a permissive site to grow. Several tumor-secreted factors precondition the “soil” in distant organs for the arrival and “seeding” of metastatic cancer cells, fostering the establishment of a pre-metastatic niche (PMN). In the last decades, many scientific advances have translated into cures for patients with localized tumors, but metastasis remains the Achilles’ heel of cancer therapy and is the leading cause of death of approximately 90% of cancer patients. Thus, there is a pressing need to better understand this complex process and develop metastasis-targeting therapies.

Endothelial cells (ECs) form the inner walls of the blood vasculature and are actively involved in many aspects of cancer progression and metastasis. To exit the bloodstream upon arrival in the metastatic organ, circulating cancer cells need to attach to and cross the endothelial barrier. The molecular players controlling the homeostasis and activation of quiescent ECs in the PMN, the key to preventing or granting access to disseminated cancer cells, remain poorly defined.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a protein mainly recognized as a component of the armamentarium of cytotoxic immune cells, allowing them to kill target cells expressing its cognate receptor DR5 and thereby limiting tumor initiation and metastasis. Combining in vitro EC cultures with in vivo metastatic breast cancer models on multiple murine strains targeting TRAIL, its cognate receptor DR5 or TRAIL decoy receptors (DcR1 and DcR2), we have uncovered a novel angiocrine function of the TRAIL pathway. Unexpectedly, ECs at the PMN co-express both TRAIL and DR5 intracellularly, where their interaction is required to block DR5 signaling and preserve a tight and quiescent vascular phenotype. In the absence of endothelial TRAIL, DR5 activation induces EC death and nuclear factor κB (NF-κB)/p38-dependent EC adhesiveness, altogether compromising vascular integrity and promoting inflammatory cell recruitment, breast cancer cell adhesion, and metastasis. Consistently, both downregulation of endothelial TRAIL at the PMN by tumor-secreted factors including vascular endothelial growth factor A (VEGF-A) and placental growth factor (PlGF), as well as the presence of DcR1 and DcR2 favor metastasis. In contrast, exogenous re-expression of TRAIL in ECs via Trail mRNA delivery with endothelium-targeting lipid nanoparticles (LNPs) protected from metastasis.

In conclusion, this doctoral thesis discloses an intracrine mechanism whereby TRAIL blocks DR5 signaling in quiescent endothelia, acting as a physiological gatekeeper of the vascular barrier function, which is overruled by the tumor during the formation of the PMN.