I’m thrilled to sit down with Ivan Kairatov, a renowned biopharma expert whose extensive experience in research and development, coupled with a keen understanding of tech and innovation, has positioned him at the forefront of groundbreaking advancements in cancer treatment. Today, we’re diving into the complex world of translocation renal cell carcinoma (tRCC), a rare and aggressive kidney cancer that primarily affects children and young adults. Our conversation explores the fascinating role of RNA in driving cancer growth, the discovery of molecular hubs as key players in tumor development, innovative tools to dismantle these structures, and the potential for new, precise therapies that could change the landscape of treatment for tRCC and beyond.
Can you start by explaining what translocation renal cell carcinoma, or tRCC, is and why it poses such a significant challenge in terms of treatment?
Absolutely, Julia. Translocation renal cell carcinoma, or tRCC, is a rare subtype of kidney cancer that’s particularly devastating because it often strikes children and young adults. It’s driven by genetic abnormalities where parts of chromosomes break and fuse incorrectly, creating hybrid genes known as oncofusions. These oncofusions, particularly involving a gene called TFE3, lead to aggressive tumor growth. What makes tRCC so tough to treat is the lack of effective therapies—standard treatments like chemotherapy or targeted drugs often fall short because this cancer operates through unique mechanisms that we’re only now beginning to understand. The poor outcomes for patients highlight the urgent need for novel approaches.
What sets tRCC apart from other types of kidney cancer, and how does that impact the way we approach it?
Great question. Unlike more common kidney cancers, such as clear cell renal carcinoma, tRCC is defined by these specific chromosomal translocations leading to oncofusion proteins. These fusions hijack cellular processes in a way that’s distinct, particularly by altering how genes are turned on or off to promote rapid, uncontrolled growth. This difference means that therapies effective for other kidney cancers often don’t work for tRCC. It pushes us to focus on the molecular underpinnings—like the role of RNA and protein interactions—that are unique to this disease, rather than relying on a one-size-fits-all approach.
Your research highlights RNA playing an unexpected role in cancer cells, almost like a builder. Can you unpack that analogy for us?
I love that analogy because it really captures what’s happening. Normally, RNA is thought of as a messenger, carrying instructions from DNA to make proteins. But in tRCC, we’ve found that RNA takes on a structural role, acting like a construction worker. It helps assemble these liquid-like structures in the cell nucleus called droplet hubs or condensates. These hubs are essentially command centers where key molecules cluster together to switch on genes that drive cancer growth. It’s a radical shift in how we view RNA—not just as a passive player, but as an active architect of disease progression.
What exactly are these droplet hubs, and why are they so critical to the growth of tumors in tRCC?
These droplet hubs are fascinating. They’re dynamic, liquid-like clusters within the cell nucleus, formed through a process called phase separation—think of oil droplets forming in water. In tRCC, the oncofusion proteins recruit RNA and other molecules to create these hubs, which then act as hotspots for gene activation. They concentrate the machinery needed to turn on cancer-promoting genes, essentially supercharging tumor growth. Without these hubs, the cancer’s ability to sustain itself would be severely disrupted, which is why they’re such a critical target for us.
You’ve identified a protein called PSPC1 as a key stabilizer of these hubs. How does it contribute to making these structures more dangerous?
PSPC1 is like the glue that holds these droplet hubs together. It’s an RNA-binding protein that interacts with the oncofusion proteins and RNA scaffolds, reinforcing the structure of these condensates. By stabilizing them, PSPC1 ensures that the hubs remain functional and efficient at activating growth-promoting genes. This makes the tumors more aggressive because the hubs become more resilient and harder to break down naturally. Understanding PSPC1’s role gives us a specific target to disrupt this dangerous setup.
Let’s dive into the cutting-edge tools you used to uncover these mechanisms. How did technologies like CRISPR help in mapping out this process?
CRISPR has been a game-changer for us. It’s a precise gene-editing tool that allowed us to tag the oncofusion proteins in patient-derived cancer cells. By doing so, we could track exactly where these proteins were going inside the cell and see how they were forming these droplet hubs. It gave us a real-time view of their behavior and interactions, which was critical for piecing together how they drive tRCC. Without CRISPR, we’d be working in the dark on a lot of these molecular movements.
You also used a method called SLAM-seq. Can you explain how that added to your understanding of gene activity in these cancer cells?
Absolutely. SLAM-seq is a powerful sequencing technique that lets us measure newly synthesized RNA, essentially showing us which genes are being actively turned on or off as these droplet hubs form. In tRCC, it helped us identify the specific genetic targets that the oncofusion proteins were controlling through these hubs. It’s like getting a snapshot of the cancer’s playbook—knowing which plays are being called and when. This detailed insight was crucial for linking the hubs directly to tumor growth.
Beyond just observing, you’ve developed a tool to dissolve these hubs. Can you walk us through how this molecular switch operates?
I’m really excited about this part. We engineered a nanobody-based chemogenetic tool, which is essentially a designer switch to target these hubs. The nanobody—a tiny fragment of an antibody—binds specifically to the oncofusion proteins within the hubs. It’s paired with a dissolver protein that, when activated by a chemical trigger, disrupts the condensate structure, causing the hub to ‘melt’ apart. When this happens, the cancer cells lose their ability to activate growth genes, and tumor progression halts. It’s a precision strike at the heart of the cancer’s machinery.
Seeing that dissolving these hubs stopped tumor growth in lab cells and mice must have been thrilling. What did those results mean to you and your team?
It was incredibly exciting, Julia. In the lab, we saw that breaking down these hubs directly stopped the cancer cells from growing, and in mouse models, tumor progression was significantly slowed or even halted. It felt like a major validation of our hypothesis—that these droplet hubs are indeed the engine of tRCC. More importantly, it gave us hope that we’re on the right path toward a therapy that could make a real difference for patients who currently have very few options. It’s a proof of concept that targeting condensates could be a whole new way to fight cancer.
Looking ahead, what is your forecast for the future of therapies targeting these molecular hubs in tRCC and other cancers?
I’m very optimistic about where this is heading. The ability to target droplet hubs opens up a completely new frontier in cancer treatment, not just for tRCC but potentially for other cancers driven by similar fusion proteins, especially in pediatric cases. I believe we’ll see more research into condensate biology over the next decade, leading to therapies that are far more precise and less toxic than current options. If we can refine tools like our molecular switch and translate them into clinical settings, we could fundamentally change outcomes for patients facing these aggressive diseases. It’s a challenging road, but the potential impact keeps us pushing forward.
