Pilot Projects

Advances in cancer detection and treatment have led to a growing population of survivors—18.6 million in the U.S. as of 2025, projected to exceed 22 million by 2035. While this represents a major public health success, it introduces a critical challenge: the rising burden of multiple primary cancers (MPC). Approximately one in twelve cancer survivors will develop a second primary malignancy, and among those with two or more
cancers, more than half die from subsequent malignancies. Known MPC risk factors include younger age at first cancer, lower stage, prior chemotherapy or radiation, adverse lifestyle behaviors (smoking, obesity, alcohol), and inherited genetic susceptibility. However, the role of environmental exposures remains largely unexplored. Per- and polyfluoroalkyl substances (PFAS) are persistent chemicals detected in nearly the entire global population. PFAS accumulate in the body for years and have been linked to kidney and testicular cancers, with emerging evidence for other malignancies. Mechanistic studies implicate PFAS in carcinogenesis through oxidative stress, endocrine disruption, and interference with DNA repair. Despite these findings, no studies have evaluated PFAS in relation to MPC, leaving a critical gap in understanding environmental contributions to cancer survivorship. This pilot study will leverage existing PFAS measurements in the Multiethnic Cohort (MEC) to examine whether circulating PFAS concentrations measured prior to diagnosis are associated with MPC risk and whether associations vary by demographic,
clinical, lifestyle, and genetic factors. We will analyze data from three nested case-control studies totaling 565 MPC cases, 2,858 first primary cancer cases, and 3,861 cancer-free controls. Findings will provide the first quantitative estimates of PFAS–MPC associations, identify subgroups with heightened vulnerability, and inform larger hypothesis-driven studies. Ultimately, this research will lay the foundation for interventions to reduce PFAS exposure and mitigate cancer burden among survivors.

“Microplastics (MP) have, in recent years, emerged as ubiquitous environmental pollutants that can cause detrimental effects on human health. While their presence has been confirmed in most human tissues and fluids, their role in cancer initiation and progression remains poorly understood. Preliminary findings from our group demonstrate that MP are internalized by renal cells and systemically distributed in vivo, supporting their potential to interact with renal tumor niches. Wilms Tumor (WT), the most common pediatric renal malignancy, originates from nephrogenic progenitors and is driven by cancer stem cells (CSC) expressing SIX2 and CITED1. These CSCs exhibit stemness programs, therapy resistance, and metastatic potential, making them critical targets for understanding WT biology. This proposal seeks to elucidate the mechanisms by which MP influence WT growth and progression. In Aim 1, we will utilize human WT CSCs to characterize MP uptake, routes of internalization, and downstream signaling changes, focusing on pathways regulating self-renewal, proliferation, and oxidative stress. In Aim 2, we will assess the in vivo impact of MP exposure on WT development using a mouse xenograft model, evaluating MP biodistribution, tumor growth kinetics, histological features and spatial transcriptomics. By combining in vitro and in vivo approaches, this study will allow us to determine how MP amplify stemness programs and stress-adaptive pathways in WT CSCs, and whether systemic MP exposure accelerates tumor progression. Our research has the potential to fill critical gaps in our understanding of MP-driven cancerogenicity and could inform future strategies for risk mitigation and shape public health policies”

“Wildfires expose millions of individuals to smoke, ash, carbonaceous toxins, and heavy metals. In patients with a recent lung cancer resections, exposure to wildfires is associated with reduced overall survival. Post-operative patients may be particularly susceptible to acute/chronic injury and/or cancer recurrence from inhaled toxins. Understanding the specific cellular and clinical mechanisms would enable evidence-driven interventions. The wide geographic range of wildfires hampers in-depth study; however, the historic Eaton Canyon and Palisades fires of January 2025 uniquely exposed a large population within a concentrated area and temporal period. Here, we propose a feasibility pilot study in support of a multidisciplinary R01 application aimed at elucidating i) the clinical ramifications of wildfire exposure on lung cancer surgery patients and ii) the detailed analysis of the underlying cellular mechanisms affecting alveolar epithelium exposed to vegetation and urban smoke. We hypothesize that increased post-operative complications will drive the increase in mortality seen in limited national datasets, and that exposed patients will have decreased disease-free and overall survival. In addition, we hypothesize that molecular effects of wildfire exposure can be modeled using human alveolar epithelial cells, and that identified molecular changes can then be examined in patient tissues. The ultimate goal of the R01 would be to develop clinical and molecular strategies to mitigate the negative effects of wildfire exposure. In Aim 1 of this pilot study, we will collect data from patients receiving surgery from the major Los Angeles clinical centers (USC Keck/Norris, LA General, Cedars Sinai, UCLA, and City of Hope) before and during the fires. In Aim 2, we will examine the transcriptomic and epigenomic effects on human alveolar epithelial cells exposed to wildfire smoke extracts from laboratory-controlled burning of vegetation and household smoke. The proposed pilot study work will demonstrate feasibility and generate pilot data for the planned R01.”

Cardiovascular Disease (CVD), often taking the form of coronary artery disease (CAD), myocardial infraction, and stroke, is a leading cause of death in western societies. It is generally accepted that CVD is characterized by both genetic and environmental risk factors. Exposure to traffic-related air pollutants (TRAP) has been associated with atherosclerosis in both humans and animal models; in our own studies, we have observed similar associations with CAD, and we identified a gene-environment (GxE) interaction where expression for the potentially atheroprotective TRIP4 protein is significantly downregulated in human coronary artery endothelial cells incubated with plasma from humans exposed to TRAP.  

This research proposal aims to further examine the GxE interactions between TRAP and CVD by investigating the in vivo effect of TRAP on cell-specific TRIP4 expression in a mouse exposure system. This has been complemented by their translational approach, where the GxE interaction will be independently replicated in subjects from the Multi-ethnic Cohort (MEC), which tracks over 200,000 participants from diverse backgrounds, to examine the effects on a much larger scale than previously done in literature.  

This project will serve as the foundation for future proposals that will further examine other GxE interactions that increase risk of CVD by expanding the analysis to the whole genome. This could include collaborative projects with International Mouse Knockout Project to elucidate the mechanism by which TRAP affects atherosclerosis in TRIP4 deficient mice and with USC colleagues to carry out genome-wide interaction studies for CVD, on a scale and scope never previously done.