Histologic transformation, when a cancer’s features shift dramatically and it presents as a new cancer type, can occur at any point in the course of disease or arise due to the selective pressure of cancer therapies. One of the most well-recognized examples of histologic transformation is the transformation of follicular lymphoma, a slow-growing cancer of the lymphocytes, to an aggressive lymphoma, typically a large B-cell lymphoma. Despite this being well-recognized in the clinic, understanding of the molecular changes that trigger this transformation remains limited. Dr. Parry seeks to comprehensively study the genetics underlying follicular lymphoma transformation with a goal of improving future recognition and diagnosis of transformation. She also aims to identify unique potential therapeutic targets associated with follicular lymphoma transformation.

The exploration of human tumors in their native environment is challenging, precluding a deeper understanding of how cancer and important therapeutics work.  Dr. Puleston [Bakewell Foundation Innovator] is developing new ways to investigate human cancer by keeping tumor-bearing organs alive outside of the body, allowing for the experimental study of tumors within human tissues. Employing this approach to study hepatocellular carcinoma (HCC), one of the most lethal forms of liver cancer, Dr. Puleston will expose HCC-laden livers to immunotherapy drugs and metabolic tracers to reveal the metabolic landscape of HCC cancers and how tumor metabolism is shaped following drug treatment. Through the study of tumors and anti-cancer agents in situ, Dr. Puleston hopes to elucidate new pathways with therapeutic potential and novel strategies to optimize existing therapeutics.

Ammonia, a waste product of cellular activity, is cleared from the body by the liver and kidneys through a process known as the urea cycle. During the urea cycle, ammonia is converted to urea, and arginine (an amino acid) is generated. When liver cells become cancerous, the urea cycle pathway stops functioning and cancer cells must import arginine from outside the cell. When cancer cells are prevented from importing arginine (via removal of arginine from the diet or genetic removal of the transporter), tumors do not grow, suggesting that arginine is critical for cells. However, the function of arginine in the cell is unclear. Using mass spectrometry and mathematical modeling, Dr. Lesner will identify the fate of arginine as it is metabolized by liver cancer cells in mouse models, and investigate how this is altered by various genetic mutations. Additionally, he will examine how restricting arginine from the diet genetically alters the liver and tumor cells. By understanding how disruption of this metabolic pathway influences liver cancer growth in the context of specific cancer drivers, Dr. Lesner aims to inform new therapeutic strategies. Dr. Lesner received his PhD from The University of Texas Southwestern Medical Center, Dallas and his BA from the University of Wooster, Wooster, Ohio.

 

Neutrophils are important anti-microbial cells within the innate immune system. Recently, it has been shown that neutrophils can perform diverse functions, taking on both pro-inflammatory and pro-healing roles in response to tissue injury or insult. Dr. Siwicki's [Dale F. and Betty Ann Frey Fellow] goal is to understand how different neutrophil subtypes or states function to balance inflammatory versus regenerative processes, ultimately influencing tissue health and cancer. This work has the potential to uncover the basis of neutrophils' pro-tumor versus anti-tumor functions and could open the door to therapeutic targeting of specific neutrophil behaviors in order to improve clinical outcomes in cancer. Dr. Siwicki received her PhD from Harvard Medical School, Boston and ScB from Brown University, Providence.

 

Abnormal interactions between our immune system and our gut microbes can lead to inflammation that drives colon and gastric cancer growth. Dr. Brian [HHMI Fellow] is investigating how the immune system recognizes and responds to these microbes, and how these interactions contribute to abnormal inflammation that can fuel cancer growth. Microbiota-immune interactions have been generally studied in the context of "clean" laboratory mice, but these models do not fully capture human immunology and the complex interplay between host cells and foreign microbes. To overcome this, Dr. Brian plans to study these interactions in "dirty" mice, colonized by a diverse community of microbes as well as pathogens. He will then use laboratory mice with more defined microbial communities to test how recognition of specific microbes by the immune system is regulated and how disruptions to this regulation contributes to inflammation. Dr. Brian received his PhD from the University of Minnesota, Twin Cities and his BS from the University of California, Santa Barbara.

 

Dr. Freije [Berger Foundation Fellow] is studying how the genetic diversity of hepatitis B virus (HBV) is shaped by its need to replicate and interact with specific host genes. Current antiviral therapeutics for HBV merely suppress infection and do not cure disease; as a result, patients with chronic HBV infection are at risk of developing liver cancer. Dr. Freije plans to uncover essential genomic regions that HBV needs to survive and persist, as well as those that counteract host genes that function to restrict these activities. This approach could provide insight into the progression of disease and has the potential to identify new antiviral therapeutics and ultimately reduce the incidence of HBV-associated liver cancer.