Abnormal interactions between our immune system and our gut microbes can lead to inflammation that drives colon and gastric cancer growth. Dr. Brian 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. Cote is exploring embryonic development to better understand how cells cooperate and build complex tissues. Since cancer cells often erroneously redeploy developmental programs and behaviors, her research into how neighboring cells align will yield insights into how cancerous cells metastasize and invade other tissues. Dr. Cote is combining tissue-specific genetic manipulations and laser cell ablations with live imaging during Caenorhabditis elegans digestive tract development to reveal how intracellular organization in one cell type can influence the alignment, polarity, and function of cells in the neighboring tissues.

Kaposi's sarcoma herpesvirus (KSHV) is a human oncogenic virus and the causative agent of cancers including Kaposi’s sarcoma, primary effusion lymphoma, and Multicentric Castleman disease. The related human herpesvirus Epstein-Barr Virus (EBV) is even more prevalent than KSHV, and is linked to cancers including Burkitt’s lymphoma, Hodgkin’s lymphoma, and nasopharyngeal carcinoma. Dr. Didychuk [The Rhee Family Breakthrough Scientist] is investigating the mechanisms by which KSHV co-opts the cellular host machinery to produce its own gene products in a manner distinct from other viruses and host cells. A molecular understanding of how herpesviruses hijack the late gene transcription machinery will reveal new therapeutic weaknesses in the viral lifecycle and allow for structure-guided design of novel anti-viral drug targets.

Earlier cancer detection usually means a greater chance of remission or cure, but cost-effective and highly specific cancer screening is not yet available for most cancers. More than 90 percent of cancers harbor aneuploidy, an abnormal number of chromosomes in a cell; this abnormality is highly specific for cancer and can be detected with DNA sequencing. Dr. Dudley [Gordon Family Physician-Scientist] is developing a new approach for detecting cells with abnormal amounts of DNA, which could identify cancer sooner. He aims to apply this approach to urine and Pap smear samples to create an inexpensive and sensitive screening test for bladder, ovarian and endometrial cancers.

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.

Dr. Kalish is studying a rare hereditary syndrome called Beckwith-Wiedemann syndrome (BWS), which increases the risk of children developing kidney and liver cancers. These individuals have epigenetic changes on chromosome 11 that are found in other types of cancers. Epigenetic markers modify DNA so gene expression is turned on or off; changes in this process can cause cancer. By understanding how cancer is triggered in BWS, Dr. Kalish aims to identify pathways that can be targeted for the development of new treatments both for BWS patients and for others with cancers that have similar epigenetic changes. As a physician-scientist, Dr. Kalish established the BWS Registry, which compiles both clinical data and patient samples, and created the first human cell-based models of BWS.

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.

Dr. Lin [Walter Isaacson Fellow] is studying how hepatitis C virus (HCV) rewires cell biology and causes liver cancer. Modern HCV antiviral therapies are effective in curing hepatitis, but puzzlingly, recovered patients sometimes still develop cancer. This suggests that infection and subsequent inflammation permanently alter liver cells, but how this leads to cancer remains unclear. Dr. Lin is developing a CRISPR-based molecular "recorder" to determine whether cells that become more cancer-like have a history of infection and inflammation. This technology could identify genes that predispose healthy liver cells to infection, chronic immune stimulation, and transformation to cancer cells, which could point to potential therapeutic targets to interrupt the development of liver and other cancers.

Mitochondria, the “power plants” of the cell, carry their own DNA that encodes proteins important to producing the energy necessary to run a normal cell. Most cancers also depend on mitochondria to promote the growth and division of tumor cells. Dr. McFadden has shown that a form of thyroid cancer called Hürthle cell carcinoma carries mutations in the mitochondrial DNA, which are maintained in primary tumors and metastases resected from the same patients. He will study energy metabolism in Hürthle cell cancers by feeding the tumors isotope forms of nutrients (tracers) that are used to produce energy and support cell growth. The tracers can be visualized to reveal how metabolism is re-wired in these tumors and to identify novel ways to target altered mitochondrial metabolism in cancers with such genetic mutations. 

New technologies developed in the last decade have enabled chemotherapy to be delivered directly to lung tumors intratumorally in contrast to systemic delivery that affects the whole body. Recent studies have shown a partial or complete response ratio of 71% with significantly fewer side effects for patients treated intratumorally with cisplatin. Dr. Mori is modeling cisplatin pharmacodynamics following injections, taking into consideration the heterogeneity of the tumor microenvironment. This research aims to optimize drug delivery strategy to enhance targeting tumor cells while reducing side effects. 

Using segmented high-resolution CT images, Dr. Mori assigns a set of features to each voxel of the tumor (diffusivity, clearance rate, and intracellular threshold concentration needed to induce cell apoptosis). He then simulates the competing physical mechanisms inside the tumor to assess the total tumor volume with an intracellular concentration above the threshold to estimate the minimal required dose based on the tumor morphology and the number of injections. The model is implemented using MatLab.