Cells have a built-in defense system that detects double-stranded RNA (dsRNA), a molecule often associated with viruses. Although this system evolved to fight microbial infections, activating it can also help the body recognize and attack cancer, especially when combined with treatments that make tumors easier for immune cells to detect. However, tumors can escape this immune pathway by producing high levels of a protein called ADAR, which edits dsRNA by changing one of its building blocks, adenosine, into inosine. These edits prevent the dsRNA from being recognized, allowing cancer cells to stay hidden even during treatment. Dr. Nichols’ [Merck Fellow] research aims to understand how these RNA changes block immune detection and to identify which RNA molecules are most likely to trigger an immune response. By uncovering how cancer cells use this editing process to escape detection, he hopes to support the development of better immunotherapy treatments. Dr. Nichols received his PhD from the University of Colorado, Anschutz Medical Campus, Aurora, and his BA from Lewis and Clark College, Portland.

“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.

Despite being necessary for life, gene expression is dangerous. It forces the double-stranded DNA helix to unwind and separate, so that one strand can be used as the template to synthesize an RNA molecule—the cousin of DNA that brings genes to life. This process leaves the opposite strand exposed and vulnerable to accidental damage and mutation, which can then cause cancer. Dr. MacDonald’s [Connie and Bob Lurie Fellow] work will systematically check various features of RNA molecules, looking for characteristics that cause an RNA sequence to aberrantly stabilize on its template DNA, prolonging the vulnerable exposure of the opposite DNA strand. Using a new kind of microscopic RNA imaging that she developed, she will find the cellular proteins responsible for removing pathologically stable RNA molecules from DNA. Uncovering the molecular features that promote gene expression-driven DNA damage will deepen our understanding of the origins and development of all cancers. Dr. MacDonald earned her PhD from the University of Toronto, Toronto, and her BS from the University of British Columbia, Vancouver.

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 [Sijbrandij Foundation Fellow] received her PhD from George Washington University, Washington D.C., and her BS from National University of Singapore, Singapore.

Many bacteria naturally colonize tumors, inspiring an emerging class of microbial therapeutics that can be modified to specifically deliver drugs into cancer tissue. In one promising drug delivery strategy, bacteria are engineered to efficiently transfer bespoke molecular cargo into human cells through bacterial membrane channels called secretion systems. Although many kinds of bacterial secretion systems exist, few have been studied well enough to be used in delivery platforms. Dr. Lodwick [National Mah Jongg League Fellow] plans to investigate the structure and function of a specific secretion system in a bacterium called Rickettsia parkeri. Understanding how and when its components assemble into a cargo delivery machine may aid the development of new bacteria-based cancer therapies. Dr. Lodwick received her PhD and MS from the University of Chicago, Chicago, and her BA from Wellesley College, Wellesley.

Dr. Chen is genetically re-engineering cancer-infecting viruses so that, once inside a tumor cell, they flip on a built-in “self-destruct” circuit called pyroptosis. This explosive form of cell death not only wipes out the infected cell but also broadcasts an alarm that rallies the immune system against the whole tumor. By pairing this viral upgrade with an ultrasound trigger, Dr. Chen aims to turn treatment-resistant pancreatic cancer—and, ultimately, other solid tumors—into diseases the immune system can eradicate. Dr. Chen received his PhD and MS from Zhejiang University, Hangzhou, and his BS from Southwest Jiaotong University, Chengdu.

Dr. Chan’s [Sijbrandij Foundation Fellow] research focuses on gamma delta T cells, an unusual and understudied population of immune cells. While gamma delta T cells have strong antitumor activity, they are most highly stimulated not by cancer cells but by signals produced by microorganisms. Dr. Chan’s work examines the mechanisms by which gamma delta T cells detect and respond to leukemia versus pathogenic microorganisms, and how infection with these microorganisms subsequently impacts the trajectory of leukemia. This is particularly relevant to patients undergoing conventional cancer treatments (e.g., chemotherapy) that suppress the immune system, rendering them susceptible to infection. Furthermore, gamma delta T cells are capable of both rapid and long-term responses against their targets, which positions them as a tool to treat initial cancer as well as prevent disease recurrence. Dr. Chan received her PhD from Yale University, New Haven, and her BS from the University of California, Los Angeles.

Radiopharmaceuticals, or drugs that contain radioactive forms of chemical elements, have transformed cancer diagnosis and treatment. Radioactive copper and manganese, for example, play a crucial role in PET imaging, while radioactive lutetium is used to deliver targeted radiation to cancer cells. While these radiometals have tremendous potential, however, their application is hindered by a lack of efficient “chelators,” or molecules that can securely bind radiometals in the human body. Computational protein design offers a solution by engineering protein-based chelators optimized for radiometal coordination, stability, and biocompatibility. Using advanced protein modeling, Dr. Klauser [Marilyn and Scott Urdang Quantitative Biology Fellow] will develop chelators for radiometals, improving diagnostic imaging and advancing lutetium-based radiotherapies. While this work is applied to HER2-positive gastric cancer, these strategies have broad applications across various cancer types, ultimately enhancing precision oncology and expanding radiopharmaceutical utility.

This research develops a computational strategy to design stable, compact metal-binding proteins for radiopharmaceuticals, enabling fusion with therapeutic antibodies. Using diffusion models, such as RFdiffusion, thousands of protein backbones are generated for metals like copper and manganese. Sequences are assigned via ProteinMPNN, filtered for stability and binding with AlphaFold 3. For rare lanthanides, symmetric duplication of known binding motifs is used. This approach streamlines the discovery of stable scaffolds for radiopharmaceutical applications.

Many cancer mutations occur in regions of the human genome that do not code for proteins. These non-coding regions serve as vital regulators of gene expression; mutations in these regions contribute to various hallmarks of cancer. Elucidating these regulatory elements and their malignant variants is critical for advancing our understanding of cancer biology and fostering precision medicine. Deep learning sequence models can substantially enhance our grasp of the regulatory genome in both health and disease. To this end, Dr. Wang aims to combine generative AI models with single-molecule regulatory genomics to uncover the principles that underlie the cancer regulatory genome at unprecedented resolution and precision. 

With single-molecule regulatory genomics, Dr. Wang will develop a deep generative AI model to learn the probability landscape of the single-molecule regulatory genome. By taking any DNA sequence as input, the deep generative AI model can generate diverse configurations of single-molecule chromatin states.

Macrophages are a major component of the body’s first line of defense, acting as sentinel cells that detect and respond to threats. One powerful trait of macrophages is their ability to modulate their response based on previous exposure to stimuli. In cancer, this adaptability can steer macrophages either to fight tumors or to protect them, depending on prior experiences. This phenomenon is often referred to as “macrophage memory.” Though macrophage memory is increasingly recognized as a factor influencing cancer progression and treatment outcomes, the mechanisms that allow macrophages to retain this memory remain unclear. Dr. Park hypothesizes that exposure of macrophages to certain stimuli leads to lasting changes in the structure of their DNA. She will combine both experimental and computational approaches to elucidate how this memory forms and how it affects the expression of immune-related genes. By uncovering the principles of macrophage memory formation, she will lay the groundwork for strategies to reprogram macrophages, potentially enhancing anti-tumor immunity and improving cancer therapy.

Dr. Park will use machine learning–aided genome modeling, leveraging bulk Hi-C data, to reconstruct 3D chromosome structures and validate them with deep learning–based image analysis. This framework will infer single-cell 3D chromosome structure in macrophages. Dr. Park will also quantify nuclear speckle–mRNA spatial relationships using microscopy and develop mathematical models of gene regulation that incorporate transcription factor activity. This integrative approach will reveal how chromosome structure shapes macrophage immune memory and functional response in cancer.