Skin cancer is the most common type of cancer worldwide, and sun exposure is known to be one of the main risk factors for developing skin cancers. Melanin pigment gives our hair, eyes, and skin their color, and it also shields skin cells from the carcinogenic effects of sun exposure. Combining just one enzyme (tyrosinase) and two substrates (oxygen and tyrosine) in the lab results in the generation of melanin—yet we know that dozens of other proteins affect pigmentation in humans. How does a process that requires so few components in vitro utilize these other factors in the human body? Dr. Adelmann’s work focuses on the cellular and biochemical contributors to human pigmentation, a clearer understanding of which will facilitate chemopreventative interventions for skin cancer that manipulate or mimic the anti-cancer properties of pigmentation. Dr. Adelmann received his PhD from Massachusetts Institute of Technology and his BA from Rice University.

Immunotherapies that rely on reinvigorating T cells to patrol the body, detect cancerous cells, and eliminate them have shown the potential for long-lasting cures. Despite their initial success, however, immunotherapies have been effective only for some cancers and for some patients. To improve outcomes, Dr. Birnbaum has developed a new method to match T cells with their antigen targets on cancer cells by engineering viruses to use T cell recognition as a means of cell entry. This technology will be applicable to a wide range of cancers, including ones for which immunotherapy is not currently effective.

Dr. Cissé [Merck Fellow] aims to define the functional importance of nutrient sensing within the tumor microenvironment. How cells sense and adapt to the availability of nutrients in their environment is incompletely understood, but one key pathway is the signaling system anchored by the mTORC1 kinase. The mTORC1 kinase regulates cell growth and metabolism in response to nutrients such as amino acids and glucose. Aberrant mTORC1 signaling is implicated in several cancers, including melanoma, known to be heavily influenced by factors in the microenvironment such as nutrient availability. Dr. Cissé aims to understand how tumor metabolism senses and responds to varying nutrient levels, which will be essential for developing novel therapeutic targets.

Dr. Gola [National Mah Jongg League Fellow] is investigating how tissue regenerates the right cell type, at the right place. Effective cell-cell communication and cell-spatial organization are critical to maintaining organ function and homeostasis. Dr. Gola will use skin as a model tissue to understand how immune cells are organized and how they communicate with resident stem cells while maintaining tolerance and providing protection. When these interactions are disrupted, they can lead to cancers and other hyper-proliferative disorders. Unraveling the mechanisms that govern healthy immune-stem cell crosstalk and what goes wrong in disease may lead to new therapeutics for skin cancers.

Immune checkpoint inhibitors (ICI), like anti-PD-1 therapy (αPD-1), have transformed clinical oncology by inducing long-term remissions, even in metastatic disease. However, fewer than 40% of cancer patients achieve such long-term remission with αPD-1, and immune-related toxicity limits more aggressive combined approaches, such as anti-PD1 and anti-CTLA-4 therapy. The question remains why a large portion of the immune response generated by combination immunotherapy is directed towards toxicity rather than anti-tumor immunity. A better understanding of the T-cell response to ICI is needed to develop safer and more effective treatment strategies. In humans, CD8+ T-cells are responsible for anti-tumor immunity. Dr. Huang [Damon Runyon-Doris Duke Clinical Investigator] is investigating the immune responses of different types of CD8+ T-cells to αPD-1 and whether they play a role in determining clinical efficacy and immune toxicity.

Cutaneous squamous cell carcinoma (cSCC) is the second most common cancer in the U.S. While most cases are caught early and cured with excision, this cancer is more aggressive in the organ transplant recipient (OTR) population, with higher rates of recurrence and metastasis. Treatment options are severely limited in these cases. OTRs require immunosuppression, which is linked to cSCC aggression, but the underlying molecular and cellular mechanisms are poorly understood. Dr. Ji has discovered an invasive cSCC subpopulation that communicates with non-malignant cell types in the tumor’s environment. By profiling OTR tumors using cutting-edge single-cell and spatial technologies, he aims to better understand how this harmful subpopulation emerges in the immunosuppressed setting, aided by crosstalk with these neighboring cells. His goal is to develop strategies for disabling invasion and improving treatment of cSCC in both OTRs and advanced cases in the general population.

Dr. Li [The Mark Foundation for Cancer Research Fellow] studies signaling events regulating the competition between cells carrying cancer-causing mutations and normal cells during cancer initiation. Previous studies have shown that intercellular signaling between mutant and normal cells could regulate the proliferation of these cells and shape the outcome of cancer initiation. Dr. Li is adapting novel tools to identify what molecular cues are mediating this crosstalk and how they contribute to cancer growth in mouse skin. Understanding these events may guide the development of cancer prevention strategies that restrict the early expansion of mutant cell lines in skin and other tissues. Dr. Li received her PhD from Duke University and her BS from Tsinghua University.

One of the leading causes of death from cancer is metastasis, or when cancer spreads from its original tissue to other parts of the body. A gene that all humans carry, called Apolipoprotein E (APOE), plays a role in how our bodies respond to cancer, including risk of metastasis. The gene comes in one of three forms: APOE2, APOE3, or APOE4. Individuals who carry APOE2 tend to fare worse when diagnosed with melanoma, while those who carry APOE4 tend to have a much lower risk of melanoma metastasis and a much better chance of survival. (Those who carry APOE3 fall somewhere in between.) Dr. Patel is researching how APOE expression in immune cells either promotes cancer targeting, as in the case of APOE4, or cancer cell survival, as in the case of APOE2. With a better understanding of how the APOE gene affects the body's response to cancer, she hopes to improve cancer therapy by tailoring treatment to the form of APOE each patient carries.

Basal cell cancer (BCC) is the most common cancer in the United States with 2 million cases annually resulting in $5 billion in societal cost. Although the majority of BCCs are small and surgically accessible, some individuals develop frequent recurrences of BCC and suffer from severe disability related to surgery and decreased quality of life. Dr. Sarin [D.G. 'Mitch' Mitchell Clinical Investigator] will focus on a group of 100 patients who develop extreme numbers of this skin lesion, in order to identify the genetic mechanisms that contribute to cancer susceptibility. While most BCCs are thought to develop from DNA damage caused by the sun's ultraviolet rays, a patient's genetics also play a critical role in disease progression. Understanding the mechanisms that contribute to cancer susceptibility will help identify at-risk individuals so they can be monitored for earlier diagnosis and prevention. She also aims to develop new non-surgical therapies for these patients.

Immunotherapy has significantly changed how lung cancer and melanoma are treated. Unfortunately, only a small percentage of patients experience long-lasting responses. Gut bacteria have emerged as a potential predictor of how patients will respond to immunotherapy and may even be adjusted to enhance the effect of immunotherapy. Dr. Shaikh aims to identify features of the gut microbiome that correlate with immunotherapy responses. She will focus on both individual bacteria as they change over the course of treatment and the metabolites made by the entire bacterial community in the colon. The goal of this project, since gut bacteria can be modified, is to develop microbiome-based treatments to be used in combination with immunotherapy to improve response rates or overcome immunotherapy resistance for patients.