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Elucidating Mechanisms of Bladder Cancer Metastasis

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Unravelling the complexities of bladder cancer

With a focus on detecting bladder cancer at an early stage, new research aims to stop its often-deadly progression.

Health

Bladder cancer is the ninth most prevalent form of cancer in the world, with the highest mortality rates seen in some European countries. “In part, this can be explained by poor prognosis, which allows the disease to progress to an advanced stage where it is able to metastasise and invade nearby tissues,” says Prasanna Vasudevan Iyengar, a Marie Skłodowska-Curie Actions individual fellowship recipient. “In fact, bladder cancer patients tend to suffer more due to the metastasis of the cancer than from the original tumour itself.” Through the EU-funded EMBRACE project, Iyengar worked to better understand the complexities of bladder cancer. In particular, his research focused on detecting the disease at an early stage and using specific chemical inhibitors to block its progression.

New discoveries made

Iyengar’s research at Leiden University Medical Center involved performing a high-throughput screening using chemical inhibitors that target epithelial-mesenchymal transition (EMT). EMT plays a role in advanced stages of cancer, and is characterised by cells gaining motility and displaying aggressive behaviour. This in turn allows the cancer cells to metastasise to distant organs, thus spreading the disease. “Our results revealed the involvement of two notorious intracellular signalling pathways, called TGF-beta and MAPK, that enhance EMT and augment the disease’s progression,” explains Iyengar. “I also successfully identified SMURF1/2 and TRAF4, two molecular target proteins that have the potential to serve as a biomarker for the early detection of bladder cancer progression.” According to Iyengar, TRAF4 is particularly interesting as it has been shown to be overexpressed in many types of cancer. However, during bladder cancer progression, it seems to play a more protective role. “This project allowed us to uncover why this molecule has different characteristics in bladder cancer and how this could impact diagnosis and treatment,” says Iyengar.

Challenges and potential

Iyengar points out that his biggest challenge was explaining the molecular mechanisms that allow his treatment strategy to work. “Even with my expertise in studying molecules in the Ubiquitin-Proteasome System, or the cell’s recycling centre, I was only able to take a one-directional approach to the problem,” he adds. “But by collaborating with clinicians and experts in bioinformatics and structural biology, I was able to take a more multidisciplinary approach to the issue.” The approach worked. Not only was Iyengar able to successfully discover the molecular mechanisms of bladder cancer progression, he also helped establish a combinatorial treatment strategy to block advanced bladder cancer progression. But he is quick to point out that this success was only possible with the help of others. “I had the privilege of collaborating with some of the leading scientists in the field, including those at Leiden University Medical Center, to answer fundamental questions in the project,” he notes. Iyengar plans to continue his work as a senior researcher at the Netherlands Cancer Institute, one of Europe’s leading cancer research institutes. “I strongly believe that identifying specific dysregulated molecules in the Ubiquitin-Proteasome System and designing state-of-the-art tools for manipulating this system have a lot of potential in the coming years,” he concludes.

Keywords

EMBRACE, bladder cancer, cancer, cancer research, metastasise, tumour, biomarker, bioinformatics, biology

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