The immune system has the capability to destroy cancer cells harboring mutated genes. Cells display peptides derived from these mutated genes (i.e., portions of the mutant protein) on a molecule called the major histocompatibility complex I (MHC I), triggering cytotoxic T cells to eliminate the cancer cells. Unfortunately, this surveillance system is weak and often subverted by cancer cells. Dr. Lee [Suzanne and Bob Wright Fellow] aims to enhance the immunogenicity of the MHC I-displayed peptides using haptens, small molecules that elicit an immune response when attached to a larger carrier protein. By empowering the immune system, he envisions that these hapten-protein complexes will enable the repurposing of cancer drugs for which resistance has emerged. Dr. Lee received his PhD and BS from the Ulsan National Institute of Science and Technology, Ulsan.

Dr. Liu’s research focuses on discovering new drug candidates to treat pancreatic, colorectal, breast, and prostate cancers. Using advanced computational techniques to screen billions of chemical compounds, she aims to identify and develop highly specific molecules that target critical pathways in cancer cells while sparing healthy tissues. For example, she has uncovered compounds that modulate calcium-sensing receptors, which play a role in certain cancers, with reduced side effects compared to the current standard-of-care. She is now applying these insights to improve treatments that boost immune responses against tumors. Dr. Liu’s work not only strives to create new cancer therapies but also deepen our understanding of the complex interactions within tumors, paving the way for precision medicine tailored to individual patients.

In simple terms, cancer arises when some cells in our body stop cooperating with the rest and start growing uncontrollably, threatening the whole organism. This breakdown in cooperation is similar to how certain beetles (called myrmecophiles) infiltrate ant colonies and selfishly use their resources, acting like a “cheater” in a cooperative society. Both cancer cells in healthy tissue and these beetle invaders in ant colonies represent a failure of cooperation, whether among cells in an organism or individuals in a colony. Ant colonies, like multicellular organisms, rely on strict controls to function properly, and when those controls are bypassed, the whole system is at risk. By recreating a key “cheating” trait in beetles—disabling their surface chemical signals to let them sneak into ant colonies—the project aims to reveal universal principles about how cooperation breaks down and how systems might evolve defenses against such threats. These insights could help to understand the fundamental properties of cancer and how to design better strategies to stop it. Dr. Loh received her PhD from George Washington University, Washington D.C., and her BS from National University of Singapore, Singapore.

Metastatic cancers exploit cellular machinery to increase their proliferative potential and direct invasive cell migration. Specifically, cancer cells can adjust the translation of RNA into proteins to keep up with the demands of growth and metastasis. An important way that cells fine-tune their translation and quickly modulate cellular responses is through localized translation, or the translation of proteins in other areas of the cell further from the nucleus. To study the scope of localized translation, Dr. Luo has developed a highly sensitive, spatially-specific, and optically-controlled technique, which enables the quantification of translation at any given subcellular location. She will focus on understanding mechanisms of localized translation by identifying which genes are locally translated, how they are regulated, and why this process is important. Understanding the molecular mechanism of local protein synthesis could yield invaluable insights into the basis of cancer metastasis and inform therapeutic strategies. 

“Bone-deep pain” is more than a metaphor. Bones and joints are constantly monitored by sensory neurons (nociceptors) that detect damage and trigger protective pain responses. However, in bone cancer and osteoarthritis, this pain can become chronic and debilitating—especially when the bone’s rich environment is colonized by migrating metastatic tumor cells originating in the prostate, breast, or lung. Dr. Martin’s [Connie and Bob Lurie Fellow] research aims to uncover how skeletal sensory neurons are activated and remodeled in these conditions. Using neurophysiology techniques, she is mapping how skeletal neurons respond to potential triggers and testing a new hypothesis: that these neurons not only detect tumors but also influence their growth. This work may uncover new strategies for treating chronic skeletal pain. Dr. Martin received her PhD from the University of Chicago, Chicago, and her BS from St. John’s University, New York.

One of the defining features of cancerous cells is that they divide quickly. The composition of the human microbiome is also due to differences in how quickly microbes grow. How do we determine how fast cells are growing in their natural environments? Is there a way to take a ‘snapshot’ and turn it into a ‘growth rate’? More fundamentally, what limits these growth rates? These are the fundamental problems Dr. McCain is studying. He is using computational simulations, machine learning, and experiments with bacteria to identify a common set of transcriptomic and proteomic biomarkers for estimating growth rates. In addition, he is examining the biophysics of growth limitation as a function of organism size. This work will provide fundamental insights into the use of gene expression data to inform and quantify key processes, like growth rate. Dr. McCain received his MSc and PhD from Dalhousie University and his BSc from the University of Western Ontario.

Sleep problems may be a risk factor for developing certain types of cancer—lung, colon, pancreas, and breast—and may affect the progression of these cancers and the effectiveness of their treatment. Conversely, symptoms of cancer or side effects of treatment, including restless legs and obstructive sleep apnea, may cause sleeping problems, reducing quality of life. Understanding the complex relationship between cancer and sleep creates opportunities to improve health, treatment options, and quality of life. Specifically, understanding how the peripheral nervous system and the brain regulate both the timing and rhythmicity of sleep (i.e., circadian control), and the balance between time awake and growing sleep pressure (i.e., homeostatic control), could improve survival rates and the quality of cancer treatment. To this end, Dr. Moore [HHMI Fellow] aims to identify the role of circulating dietary cholesterol on sleep and to conduct a targeted genetic screen to identify peripherally secreted proteins that affect either the circadian or the homeostatic control of sleep. These results will provide a means for therapeutic interventions to ameliorate the effects of sleep disruption. Dr. Moore received her PhD from Princeton University and her MS and BS from the City College of New York.

Certain immunotherapies work by instructing macrophages, a type of innate immune cell, to attack the tumor by phagocytosing, or eating cancer cells. However, macrophages rarely eat an entire cancer cell within a solid tumor. Instead, they nibble pieces off the cancer cell, a process called trogocytosis. While phagocytosis kills the cancer cell, trogocytosis usually doesn’t – and worse, nibbling removes the markers on the cancer cell that allow the immune system to recognize it as a threat. Dr. Morrissey is studying why some cancer cells die after being nibbled while others survive, with the goal of making macrophage-activating immunotherapies more effective. Specifically, she is studying Her2-positive breast and ovarian cancers, as it has been shown that Her2 immunotherapies cause trogocytosis instead of phagocytosis. This research could enhance any immunotherapy that is designed to activate macrophage phagocytosis, improving treatment of diverse cancers like lung cancer, lymphoma, and glioblastoma.

The PABPC1 protein has diverse roles in gene expression control that span functions in mRNA stability, polyA tail length control, and translation regulation. PABPC1 gene amplifications are detected in roughly 4% of cancer samples, but it is unclear how PABPC1 fits into the picture of cancer progression. Dr. Muller [HHMI Fellow] studies the sequence preferences of PABPC1 protein to understand the mechanistic details that determine which transcripts are subject to PABPC1-mediated regulation. Connecting these sequence preferences to the mis-regulation caused by excess PABPC1 may provide a therapeutic handle for cancers that contain PABPC1 gene amplifications. Dr. Muller received his PhD from the University of California, Berkeley and his BS from Arizona State University, Tempe.

As different tissues in the body form, cells need to undergo a complex, precisely timed series of differentiation programs to form specialized cell types. Importantly, premature or delayed initiation of these programs can contribute to cancer formation. However, how timing of cellular differentiation is encoded on a molecular level is poorly understood. Dr. Noetzel [Merck Fellow] is using the protozoan parasite Cryptosporidium parvum as a simplified model of eukaryotic differentiation. After infecting the intestinal lining of a mammalian host, these single-celled parasites undergo exactly three rounds of asexual replication before collectively differentiating into gametes. These studies will investigate how this hard-wired, intrinsic developmental timer is encoded. In his project, Dr. Noetzel aims to understand how these parasites "count to three," which will inform our basic understanding of how eukaryotic cells keep track of time during development. Dr. Noetzel received his PhD from the Weill Cornell Medical College, Cornell University, New York and his MSc and BSc from Georg-August-University, Göttingen.