Decoding Mitochondrial Mysteries: From CLL to Aggressive Lymphoma
Work done in the lab of Prof. Lili Wang at City of Hope Comprehensive National Medical Center
Dr. Prajish Iyer completed a bachelor’s degree in biotechnology from Mumbai University and received a master’s in Biochemistry from The Maharaja Sayajirao University of Baroda. He earned his Ph.D. in Life Sciences from the Advanced Centre for Treatment, Research, and Education in Cancer (ACTREC) in Mumbai with Dr. Amit Dutt. During his PhD, he elucidated the function of recurrent genetic mutations in Indian gallbladder cancer, significantly advancing the understanding of this aggressive disease.
Following his Ph.D., Dr. Iyer moved to the United States for his postdoctoral fellowship at the City of Hope under Dr Lili Wang, where he has been delving into the complex mechanisms of how chronic lymphocytic leukemia (CLL) progresses to the more aggressive Richter’s Transformation (RT). Currently, Dr Iyer is a Staff-Scientist at City of Hope, where their research involves uncovering the metabolic changes in RT, developing innovative models to study this transformation, and exploring new treatment possibilities.
Author Interview
How would you explain your research outcomes to the non-scientific community?
Imagine a factory that produces all the goods a city needs to function smoothly. If the machinery in the factory is faulty, the production process becomes inefficient, resources are wasted, and eventually, the factory might shut down completely. Just like this factory, mitochondria are the powerhouses of our cells, providing the energy they need to function correctly. In cancer, mitochondrial dysregulation is akin to the faulty machinery in the factory. The mitochondria in cancer cells stop working correctly, causing these cells to change the way they produce and use energy. This malfunction allows cancer cells to grow uncontrollably, spread faster, and survive in conditions that typically kill healthy cells. By understanding and repairing these faulty “factories” in cancer cells, we can cut off their energy supply, making it harder for them to grow and spread. This approach could lead to new, more effective treatments that target the foundation of cancer cell survival.
Mitochondria, often referred to as the powerhouses of the cell, are specialized organelles found in nearly all eukaryotic cells that produce the energy cells need to function. This energy is generated through oxidative phosphorylation, which occurs within the inner membrane of the mitochondria. Essentially, mitochondria convert the energy stored in nutrients into adenosine triphosphate (ATP), the cell’s energy currency, which powers various cellular processes. Mitochondrial dysregulation in cancer means that the mitochondria, the cell’s energy factories, are not working correctly in cancer cells. This malfunction causes the cancer cells to change how they produce and use energy, often making them grow and spread more aggressively. By altering their metabolism, cancer cells can survive harsh conditions, resist treatment, and thrive. Understanding and targeting these changes in mitochondria can help develop new therapies to stop the growth and spread of cancer.
Richter’s Transformation (RT) is a rare but aggressive form of progression that occurs in some patients with chronic lymphocytic leukemia (CLL). In this transformation, the slow-growing CLL cells suddenly change into a much more aggressive form of lymphoma, most commonly diffuse large B-cell lymphoma (DLBCL). This transformation is characterized by a rapid increase in cancer cell growth and resistance to standard CLL therapies, leading to a poor prognosis. Understanding the mechanisms behind this transformation is crucial for developing targeted therapies to improve outcomes for patients with RT.
“We have developed a novel murine model that mimics human RT.”
How do these findings contribute to your research area?
One of the major challenges in understanding Richter’s Transformation (RT) is its rarity and aggressiveness. Because RT is uncommon, gathering enough patient samples for comprehensive studies is difficult, limiting our understanding of the genetic and molecular mechanisms driving the transformation from chronic lymphocytic leukemia (CLL) to RT. Another significant challenge is the heterogeneity of the disease. RT can arise through various genetic pathways and mutations, making pinpointing a single cause or treatment strategy difficult. This complexity necessitates extensive and detailed genomic analyses, which are time-consuming and expensive.
Additionally, there is a lack of effective preclinical models that accurately mimic human RT. While progress has been made in developing animal models, they often do not capture the full spectrum of the disease seen in patients, limiting our ability to test and refine new therapeutic approaches. Moreover, RT is highly resistant to conventional therapies used for CLL, necessitating the development of novel targeted treatments. This requires a deep understanding of the metabolic and signaling pathways involved in RT, which remains an ongoing area of research.
What was the exciting moment during your research?
We have developed a novel murine model that mimics human RT. This model is crucial for studying the disease’s progression and testing potential therapies in a controlled environment. We will use this model to validate our findings from the metabolomic and genomic analyses and to explore the effectiveness of targeting these pathways.
What do you hope to do next?
I plan to have my research group one day, starting by first finding an independent position and achieving tenure. My group’s objective will be to develop better strategies to address aggressive transformations in cancer. Given my background in solid and liquid tumors, I aim to bridge the connections between these areas of oncology. By integrating insights and techniques from both fields, I hope to uncover novel therapeutic approaches and improve treatment outcomes for patients facing aggressive cancer transformations. Further, in probably ten years, I wish to win the Padma award from the government of India in the NRI category.
Where do you seek scientific inspiration from? I draw my inspiration from my work, my dedication, and myself. However, if I were to name a person, it would be my Ph.D. mentor, Dr. Amit Dutt. He instilled in me a profound sense of belief and taught me never to give up and to fight tooth and nail to win all scientific battles. Dr. Dutt guided me through various aspects of scientific endeavors, whether it be presentations, emails, or experiments, shaping me into the researcher I am today. Since I have been in the US for a long time now, my current mentor, Dr. Lili Wang, exemplifies the never-give-up attitude and continues to inspire me daily.
How do you intend to help Indian science improve? Firstly, I can mentor and guide young scientists in India, sharing my knowledge and experiences to help them develop their skills and pursue groundbreaking research. This includes conducting workshops, webinars, and seminars to provide training in advanced research techniques and methodologies. Secondly, by developing and implementing strategies that target aggressive cancer transformations, I hope to contribute to more effective treatments and improved patient outcomes in India.
Reference:
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