Pancreatic ductal adenocarcinoma (PDAC) stands as one of the most lethal malignancies, notorious for its aggressive metastasis and dismal prognosis. PDAC is diagnosed at a late stage and symptoms are usually vague and non-specific in the early stages, leading to delayed diagnosis. By the time it is detected, the cancer often has advanced and spread to other parts of the body. Treatment options for pancreatic cancer are limited. Surgery, which can be a potential cure, is only an option if the cancer is detected early and hasn’t spread. However, most patients are diagnosed when the cancer is already advanced. It tends to be very aggressive. It grows and spreads quickly, which makes it harder to treat effectively. Chemotherapy and radiation therapy, the other standard treatments, are often not very effective against advanced pancreatic cancer. Netrin-1 a protein that in humans is encoded by the NTN1 gene. It is known for its role in axon guidance in the developing nervous system. Netrin-1 is a part of the extracellular matrix and functions as a guidance cue for neurons and their axons and dendrites, helping them to navigate and reach their target destinations during development. Netrin-1 has also been implicated in other processes such as angiogenesis (the development of new blood vessels) and cancer, where its expression can influence tumor growth and metastasis. The study of Netrin-1 and its signaling pathways can provide important insights into the understanding the molecular mechanisms underlying various diseases, including some forms of cancer and neurodegenerative disorders. In a new study published in peer reviewed Journal Cell Reports and led by Professor Darren Carpizo from the University of Rochester in New York undertook a comprehensive investigation into the role of Netrin-1 in the metastasis of PDAC, particularly focusing on liver metastasis. The team started by establishing that Netrin-1, an axonal guidance molecule, is upregulated in metastatic PDAC. They used human and murine models for this purpose, comparing Netrin-1 levels in primary tumors and metastatic sites, particularly the liver. They employed RNA sequencing (RNA-seq) and immunohistochemistry to validate the upregulation of Netrin-1 in these models. The researchers discovered that extracellular vesicles (EVs) secreted by PDAC cells carry Netrin-1 on their surface. These EVs are instrumental in priming the liver for metastasis. The research team investigated the Unc5b receptor, a dependence receptor for Netrin-1. The interaction between Netrin-1 and Unc5b was shown to be a double-edged sword; while its presence promoted metastasis, its absence triggered apoptosis in PDAC cells. This dual nature of the Unc5b receptor was harnessed to develop an anti-Netrin-1 therapeutic strategy, aiming to disrupt this ligand-receptor interaction and thereby induce cell death in metastatic cells.
They also examined the impact of these Netrin-1 carrying EVs on hepatic stellate cells (HSCs), which are crucial in forming the metastatic niche in the liver. The authors investigated the molecular mechanism of how Netrin-1 promotes metastasis. They focused on the interaction between Netrin-1 and its receptor, Unc5b, and how this influences the behavior of PDAC cells. They conducted in vitro and in vivo experiments to demonstrate that the interaction between Netrin-1 and Unc5b promotes PDAC metastasis. A significant discovery was the role of HSCs in the metastatic process. The researchers showed that Netrin-1 leads to the activation of HSCs, which then secrete retinoic acid. This retinoic acid further stimulates the expression of Netrin-1 in disseminated tumor cells, creating a feedforward loop that facilitates metastatic colonization.
Based on their findings, the researchers developed an anti-Netrin-1 therapeutic approach. They aimed to disrupt the Netrin-1-Unc5b interaction to induce apoptosis in metastatic PDAC cells. This therapeutic strategy was tested in murine models, demonstrating its efficacy in reducing metastasis and improving survival rates. The authors successfully illuminated a previously underappreciated mechanism of metastasis in PDAC, providing a deeper understanding of the disease’s biology. The identification of Netrin-1 as a central player in metastatic spread offers a novel and promising therapeutic target, potentially revolutionizing the treatment paradigm of PDAC. Moreover, the use of anti-Netrin-1 therapy, as demonstrated in murine models, provides a beacon of hope in a disease notoriously resistant to conventional treatments. By exploiting the unique dependence receptor mechanism of Unc5b, this therapeutic approach heralds a new era in targeted cancer therapy, one that is more precise and potentially more effective. Furthermore, the authors’ findings extend beyond PDAC, potentially impacting the broader field of oncology. The elucidation of a feedforward mechanism involving Netrin-1 and HSCs in metastasis could be a recurrent theme in other malignancies, thus opening new avenues for research and therapy in various cancer types. Lastly, the study underscores the importance of the tumor microenvironment in cancer progression, particularly the role of EVs in intercellular communication and metastasis. This insight could lead to novel strategies targeting the microenvironmental components of tumors, thereby disrupting the metastatic process at multiple levels. Professor Darren Carpizo and his associates concluded that targeting Netrin-1 could be a promising strategy for combating metastatic PDAC, particularly for liver metastases.
Dudgeon C, Casabianca A, Harris C, Ogier C, Bellina M, Fiore S, Bernet A, Ducarouoge B, Goldschneider D, Su X, Pitarresi J, Hezel A, De S, Narrow W, Soliman F, Shields C, Vendramini-Costa DB, Prela O, Wang L, Astsaturov I, Mehlen P, Carpizo DR. Netrin-1 feedforward mechanism promotes pancreatic cancer liver metastasis via hepatic stellate cell activation, retinoid, and ELF3 signaling. Cell Rep. 2023 ;42(11):113369. doi: 10.1016/j.celrep.2023.113369.