Department of Biochemistry and Molecular Pharmacology, Institute for Systems Genetics
New York University School of Medicine
My vision is to address cancer mechanobiology with the rigor of classical genetics together with technologies from bioengineering and concepts from biophysics. Very little is known about the fundamental mechanisms that control the physical properties of cells or how perturbations to those properties affect cell biology. This biology is crucial to pancreatic cancer, which builds up a tremendous amount of physical pressure. We have developed technologies that allow us to efficiently address these questions and I’m excited to forge ahead with this research.
Liam Holt obtained a Masters in Biochemistry from the University of Bath (UK). He then won a grant from the British Council and CSIC (Spain) to undertake cancer research at the Universidad Autónima in Madrid. He completed his PhD in the UCSF Tetrad program studying cell cycle regulation with David Morgan, and then won a Bowes Fellow position to run a lab at UC Berkeley. He joined NYU as an Assistant Professor in 2016 in the Institute for Systems Genetics. His lab uses systems biology, quantitative cell biology, biophysics, cell biology, and proteomics to understand how cells integrate information from the environment and make decisions about how to grow, divide and differentiate. His recent work focuses on the effects of physical compression on cells, and how these mechanical forces play a role in both normal biology and the pathologies of cancer progression and neurodegeneration. Dr. Holt is also passionate about science outreach and communication and is co-founder of Science Sketches (www.sciencesketches.org), a project to engage scientists to create videos that explain fundamental scientific concepts to the public.
How do cancer cells overcome mechanical compressive stress?
Physical pressure is crucial for cancer biology, but its effects remain poorly understood. When solid tumors grow confined within surrounding tissue, they build up pressure. Given that cells evolved to function in a stable mechanical environment, even slight changes in pressure perturb physiology. Normal cells and early stage cancer cells stop growing when pressure builds up, while advanced cancer cells are better able to grow and survive. This difference implies that cancer cells somehow adapt to physical pressure. This adaptation is of particular importance to pancreatic cancer, which builds up the most pressure of any tumor type. A lack of tools has prevented understanding of relationships between compression, the physical properties of cells, and cancer behavior.
“The Pershing Square Sohn Prize will allow us to fully develop our technologies to study the impacts of compression on cells and jump in with both feet to understand how this crucial element of the tumor microenvironment affects pancreatic cancer.”
We developed two new technologies to overcome this limitation: First, we created a gene that produces fluorescent nanoparticles in cells that act as tell-tales for the physical properties inside cells and how cells change when compressed. Second, we developed micro-compression chambers to precisely apply pressure to cells. We will combine these innovations to discover how pancreatic cancer cells adapt to their high-pressure environment. In preliminary studies, we found that activating mutations in KRAS change the preferred mechanical environment for cancer cells: amazingly, mutant cells grow more rapidly under pressure than without pressure. We think this explains why >95% of pancreatic cancers have this mutation. We will determine how KRAS enables growth under pressure. By determining the fundamental biology of pressure adaptation, we may discover strategies to treat this currently untreatable disease.
“For me, innovation typically arises at the nexus of fields. By bringing together ideas and expertise from diverse disciplines, the need for new technologies becomes clear. With new technologies and different ways of thinking, long-standing barriers to progress are broken down.”