The most dangerous aspect of cancer is not the initial tumor itself but its ability to move to other parts of the body, a process known as metastasis, responsible for the majority of cancer-related deaths. This journey of cancer cells from their origin to distant organs involves a sophisticated transformation, enabling them to migrate and settle in new territories. This transformation is facilitated by a process that allows cancer cells to change their characteristics, losing their stationary nature and gaining the ability to move and invade. Understanding this transformation sheds light on cancer’s elusive behavior and opens the door to potentially groundbreaking treatments targeting these cellular chameleons.
A team led by Dr. Ana-Maria Dragoi from LSU Health Shreveport, together with Madison Catalanotto, Camille Abshire, Reneau Youngblood, and Min Chu from the same institution, Joel Markus Vaz from Georgia Institute of Technology, and with the collaboration of Professor Herbert Levine of Northeastern University and Dr. Mohit Kumar Jolly from the Indian Institute of Science, has achieved a significant breakthrough in understanding cancer spread. They have discovered the essential role of a protein known as FLASH in controlling the transformation process that allows cancer cells to spread, known as the epithelial-to-mesenchymal transition (EMT).
This process is vital for cancer cells to separate from the initial tumor and move to other body parts. The team’s findings, published in the Translational Oncology journal, show how the absence of FLASH leads to cancer cells displaying mixed characteristics in which non-invasive behavior features coexist with aggressive features. Dr. Ana-Maria Dragoi highlighted the core discovery by stating, “First, we uncover that FLASH controls the epithelial stationary state of cancer cells. Now we know that the regulation is more complex and that FLASH controls multiple aspects of the cellular transformation in cancer”, pointing out its critical role in the progression and spread of cancer. Interestingly, FLASH is temporally increased in all cells as they progress through the cell cycle, and it plays a critical role in generating the scaffold proteins (histones) on which the DNA wraps around.
By utilizing advanced RNA sequencing and computational analysis, the research team identified FLASH’s unique role in suppressing stationary cell markers and affecting genes related to cell movement. They examined data from the Cancer Cell Line Encyclopedia (CCLE) to confirm the inverse relationship between FLASH expression and markers of the cell epithelial phenotype across different cancer types. In agreement with the data from their RNA sequencing, in some cancer types FLASH also inversely correlated with markers of the cancerous cellular transformation. Dr. Dragoi added, “We confirmed inverse relationships between FLASH expression and markers of both cancer invasive and cancer stationary behavior, however when cancer cells lack FLASH they are overall less aggressive”. These puzzling results suggest that FLASH plays a complex dual role in regulating cell fate, and connects with previous data showing that the most aggressive cancer cells have mixed characteristics.
This approach allowed for a detailed examination of the genetic and molecular behaviors driving cancer cell actions, making the science accessible to a wide audience and paving the way for innovative cancer treatment strategies. Understanding how FLASH controls the cell transformation process could lead to new therapeutic approaches, offering hope for more effective cancer treatments in the future. Dr. Dragoi emphasized, “These findings highlight the importance of FLASH in cancer’s ability to adapt and survive, marking it as a promising target for future therapies.” This study represents a significant step forward in our understanding of cancer biology and introduces new directions for the development of targeted cancer therapies.
JOURNAL REFERENCE
Madison Catalanotto, Joel Markus Vaz, Camille Abshire, Reneau Youngblood, Min Chu, Herbert Levine, Mohit Kumar Jolly, Ana-Maria Dragoi, “Dual role of CASP8AP2/FLASH in regulating epithelial-to-mesenchymal transition plasticity (EMP)”, Translational Oncology, 2024. DOI: https://doi.org/10.1016/j.tranon.2023.101837.
ABOUT THE AUTHORS
Dr. Ana-Maria Dragoi is an Assistant Professor in the Department of Physiology at LSU Health Shreveport. Her laboratory studies epithelial-to-mesenchymal transition regulation in the context of cell cycle progression, and intrinsic and extrinsic factors regulating cancer metastasis in the context of oncogenic reprogramming. Dr. Dragoi is a member of the American Association of Cancer Research and the American Society for Microbiology.
Dr. Mohit Kumar Jolly is an Associate Professor in the Department of Bioengineering at the Indian Institute of Science. His research integrates systems biology approaches and experimental approaches to elucidate molecular drivers of cancer metastasis and cancer therapy resistance. Dr. Jolly is the Editor-in-Chief at NPJ Systems Biology & Applications. He is a recipient of the 2022 INSA Medal for Young Scientists and the 2023 ICTP Prize winner.
Dr. Herbert Levine is a University Distinguished Professor of Physics and Bioengineering at Northeastern University. His research focuses on computational and physical modeling of epithelial-to-mesenchymal transition plasticity, genetic regulation of cell fate, and the interaction between tumors and the immune system. Dr. Levine is a member of the American Academy of Arts and Sciences and the National Academy of Sciences and the co-director of the NSF Center for Theoretical Biological Physics (CTBP) at Rice University.
