New study reveals the crucial role of LUBAC in LTβR signaling and its impact on liver cancer prognosis

Researchers from the Cancer Institute of UCL (London), the University of Cologne, the IIS Aragón and the University of Stuttgart have made a revolutionary discovery in the field of cancer biology, identifying LUBAC (Linear Ubiquitin Biding Assembly Complex) as a key element for the pro-tumorigenic signaling of the lymphotoxin β receptor (LTβR).

Researchers from the Cancer Institute of University College London (UCL), the University of Cologne, the Aragon Health Research Institute and the University of Stuttgart have made a revolutionary discovery in the field of cancer biology, identifying LUBAC (Linear Ubiquitin Biding Assembly Complex) as a key element for pro-tumorigenic signaling of the lymphotoxin receptor β (LTβR). This work, Recently published by the prestigious journal Cell Death and Differentiation, belonging to the Nature Publishing Group, has important implications for understanding the molecular mechanisms of inflammation-induced tumor development, particularly in liver cancer.

The LTβR receptor is well known for its role in the development and maturation of lymphoid organs, and is essential for the proper functioning of the immune system. However, its activation also promotes the spread and growth of tumors by activating the secretion of proinflammatory factors. Despite its importance, Until now, there was no detailed understanding of how LT signaling works.βR.

In this study, co-led by Professor Henning Walczak, Dr. Diego de Miguel and Professor Nieves Peltzer, and carried out by Dr. Yu-Guang Chen and collaborators, it was discovered that LUBAC is an essential and previously unrecognized component of the LT signaling complexβR (LTβR-SC). They found that linear ubiquitin chains generated by LUBAC facilitate the recruitment of several factors required to fine-tune LTβR signaling, cooperatively regulating the balance between canonical and noncanonical NF-κB signaling. Thus, LUBAC is responsible for generating the secretion of proinflammatory and protumorigenic cytokines upon LTβR activation by activating the canonical NF-κB pathway.

According to the study, this mechanism appears to be particularly relevant for patients with liver cancer. In this regard, as Yu-Guang Chen states: “Based on our innovative biochemical findings on LTβR signaling, we performed a bioinformatics analysis indicating that the existence of high LTβR expression together with high LUBAC expression correlates with poor prognosis in patients with liver cancer. This highlights the clinical importance of LTβR- and LUBAC-mediated inflammatory signaling.”

On the other hand, the authors demonstrate that this new mechanism described It can also be observed in other types of cancer cells besides liver cancer, suggesting that it might be a more general protumorigenic mechanism.Professor Walczak states that “in this study we redefined how LTβR signaling works and showed that it is decisive for the protumorigenic activation of NF-kB in several types of cancer.” Dr. de Miguel expresses the same opinion: “although in our study we focused mainly on liver cancer, similar mechanisms could be behind the development of other cancers that are known to be driven by inflammation. Future studies will reveal this.” Finally, Professor Nieves Peltzer highlights the immediate clinical relevance of the results shown in the study: “our findings have the potential to develop patient stratification biomarkers and therapeutic strategies targeting LUBAC activity.”

This discovery represents a significant advance in our understanding of the molecular underpinnings of LT signaling.βR and its role in cancer progression. Researchers are optimistic that this knowledge will pave the way for new therapeutic approaches to improve outcomes for patients with liver cancer.

Link to access the article: https://www.nature.com/articles/s41418-024-01355-w

Image:  Diego de Miguel, one of the principal investigators of the study