The EACR’s ‘Highlights in Cancer Research’ is a regular summary of the most interesting and impactful recent papers in cancer research, curated by the Board of the European Association for Cancer Research (EACR).
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2. Breast tumors interfere with endothelial TRAIL at the premetastatic niche to promote cancer cell seeding
Riera-Domingo, C. et al. Science Advances. 9(12): (2023).
doi: doi.org/10.1126/sciadv.add5028.
Summary of the findings
Metastasis remains the leading cause of death for cancer patients. To colonize distant organs, circulating cancer cells (CCCs) need to attach to and cross the endothelial barrier. The mechanisms controlling the homeostasis and activation of quiescent endothelial cells (ECs) in the pre-metastatic niche, key to preventing or granting access to CCCs, remain poorly defined. In their study, Riera-Domingo et al. have uncovered a novel angiocrine function of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and its cognate death receptor 5 (DR5) in ECs, acting as physiologically relevant gatekeeper of the vascular barrier integrity. Co-expression of TRAIL and DR5 in adult quiescent ECs allows them to interact intracellularly with each other, resulting in the blockade (and not in the activation) of DR5 signaling and thereby safeguarding EC survival, promoting a resting antiadhesive state, and ultimately ensuring a tight and quiescent vascular barrier. In absence of endothelial TRAIL, DR5 signaling is unleashed, compromising the integrity of the vascular barrier, promoting inflammatory cell recruitment, and favoring metastatic cell adhesion and lodging. The protective function of endothelial TRAIL was counteracted both by tumor-derived signals, which silenced TRAIL, and by TRAIL decoy receptors (DcRs), which entrap and endogenously inhibit TRAIL. Excitingly, blocking TRAIL receptors or promoting the exogenous expression of TRAIL via TRAIL mRNA delivery by endothelium-targeting lipid nanoparticles conferred protection against metastasis in pre-clinical models of breast cancer.
High TRAIL expression in quiescent ECs of certain healthy adult organs (i.e., lung and liver) holds DR5 intracellularly and prevents its activation, thereby supporting cell survival, quiescence, and a resting anti-inflammatory/antiadhesive state. Together, this ensures the stability of the vascular barrier. During cancer progression, TRAIL transcriptional downregulation in response to systemic tumor-derived factors (i.e., VEGF-A, PlGF, and others) or DcR-mediated entrapment liberates DR5 and increases DR5 availability at the cell surface of ECs in distant organs, which is sufficient to trigger its activation in a ligand-independent manner. Consequently, EC apoptosis and NF-κB/p38–mediated EC inflammation compromises vascular integrity, favoring the subsequent leukocyte recruitment and ICAM1/E-Selectin–mediated cancer cell adhesion. Altogether, tampering with the angiocrine function of TRAIL in ECs in distant organs fosters the establishment of a PMN and, subsequently, cancer cell dissemination and metastasis. (This illustration was created with BioRender)
Future impact
Besides highlighting an important mechanism that functions as gatekeeper of the endothelial lining in a healthy organ, this study has important implications regarding the use of therapeutics exploiting the TRAIL pathway. It highlights a possible divergent effect of exogenous versus endogenous TRAIL and unveils a prometastatic role of DR5 in the stroma, raising the question of whether TRAIL receptor antagonists may be more suitable than TRAIL receptor agonists in certain patients. Moreover, it provides evidence that targeting TRAIL DcRs restrains metastasis, and provides proof-of-concept that reinforcing the expression of TRAIL specifically in ECs could have therapeutic benefits against metastasis.
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Summary of the findings
Summary of the findings
