Research

Spatial, molecular, and clinical dissection of pancreatic neuroendocrine tumors

PROJECT 1. Decoding tumor-microenvironment interactions using spatial transcriptomics. Spatial transcriptomic profiling is an innovative technique that provides a comprehensive understanding of the tumor and its surrounding microenvironment at a cellular level. Through integration with traditional histology, this approach allows for the simultaneous visualization and molecular characterization of individual cells within their spatial context. In the context of tumors, spatial transcriptomic profiling enables the identification and mapping of specific gene expression patterns within the tumor cells, as well as in neighboring stromal, immune, and vascular cells. This multidimensional information sheds light on the intricate interplay between the tumor and its microenvironment, uncovering critical insights into tumor heterogeneity, immune cell infiltration, and other key biological processes. By capturing the spatially resolved gene expression landscape, spatial transcriptomic profiling holds immense promise for advancing our understanding of tumor biology and guiding the development of targeted therapeutic strategies.

NCI R21 (MPI: Heaphy & Dries; Co-I: Singhi)

PROJECT 2: Targeting Alternative Lengthening of Telomeres as a cancer-specific vulnerability. Unlimited replicative capacity is a defining hallmark of cancer, enabling tumor cells to bypass replicative senescence and telomere-driven genomic crisis. While most cancers achieve this through telomerase reactivation, a biologically distinct subset relies on a telomerase-independent mechanism known as alternative lengthening of telomeres (ALT). ALT is tightly linked to cancer-specific inactivating mutations in the ATRX–DAXX chromatin remodeling complex, making it an attractive and selective therapeutic target. This project focuses on defining and exploiting the molecular dependencies unique to ALT-positive cancers. By systematically dissecting the pathways that sustain ALT-mediated telomere maintenance, we aim to identify critical vulnerabilities that can be therapeutically targeted without affecting telomerase-positive normal tissues. Our long-term goal is to develop rational, ALT-directed therapeutic strategies that selectively impair the survival of ALT-dependent cancer cells. Targeting this cancer-specific telomere maintenance pathway has the potential to deliver more precise, effective treatments for patients with ALT-positive malignancies.

DOD Rare Cancers Research Program Idea Development Award (PI: Heaphy; Co-I: Flynn)

PROJECT 3: Alternative Lengthening of Telomeres as a prognostic biomarker in human cancer. ALT is a telomerase-independent telomere maintenance mechanism that defines a biologically distinct subset of human cancers. We have previously performed one of the largest systematic surveys of ALT to date, characterizing telomere maintenance status across more than 6,000 primary tumors spanning over 90 cancer subtypes. These and other studies have demonstrated that ALT is enriched in specific malignancies, including sarcomas, astrocytomas, pancreatic neuroendocrine tumors (PanNETs), hepatocellular carcinomas, and testicular germ cell tumors. Although the clinical impact of ALT is tumor-type and context dependent, ALT-positive cancers are frequently associated with increased genomic instability and adverse clinical outcomes, particularly in tumor types for which effective targeted therapies remain limited. Building on these foundational observations, this project focuses on rigorously evaluating the prognostic value of ALT, alone and in combination with complementary molecular and histopathologic biomarkers, across selected cancer types including PanNETs, gliomas, and sarcomas. The ultimate goal of this work is to establish ALT as a robust, clinically actionable prognostic biomarker that can improve risk stratification, inform surveillance and treatment decisions, and enable more personalized therapeutic strategies for patients with ALT-positive cancers.

Telomere dysfunction, stromal biology, and disparities in prostate cancer progression

PROJECT 4: Tissue-Based telomere length as a prognostic and risk stratification biomarker in prostate cancer. Telomere dysfunction is a key driver of genomic instability and cancer evolution. We and others have hypothesized that progressive telomere shortening in prostate cancer cells promotes the emergence of aggressive tumor clones with enhanced invasive and metastatic potential. Building on this framework, our work has established the clinical feasibility and prognostic utility of a tissue-based “telomere biomarker,” defined by increased cell-to-cell variability in telomere length among prostate cancer cells and shortened telomeres within prostate cancer–associated stromal (CAS) cells. Across multiple patient cohorts, this telomere biomarker identifies men at significantly increased risk of adverse clinical outcomes, highlighting its strong translational potential for improving prostate cancer prognostication and risk stratification. Importantly, this approach is compatible with routine pathology workflows, supporting its potential for clinical implementation. In collaboration with clinical, pathology, and epidemiology partners, we are evaluating the clinical utility of the telomere biomarker in three key decision-making contexts: (1) at the time of surgery: to refine prognostication and guide postoperative management; (2) at the time of biopsy: to improve risk stratification and inform treatment versus surveillance decisions; (3) prediction of therapeutic response: to identify patients most likely to benefit from specific treatment strategies. Collectively, this work aims to enable more precise, individualized therapeutic and surveillance strategies for men with prostate cancer.

NCI R01 (MPI: Meeker & Heaphy)

PROJECT 5. Precision risk modeling to reduce disparities in prostate cancer outcomes. Disparities in prostate cancer incidence, disease aggressiveness, and clinical outcomes remain a major challenge in healthcare. Certain groups of men experience disproportionately higher risk of aggressive disease and worse outcomes, underscoring the urgent need for improved, individualized risk assessment strategies. This project integrates genetic, cellular, tumor microenvironment, and clinical data to better define the biological and contextual factors that drive prostate cancer disparities. Prior studies have identified population-associated genetic variants, as well as differences in tumor biology and immune responses, that may influence disease progression and treatment response. Building on this foundation, we seek to identify and incorporate additional clinical, pathological, and social determinants of health that are essential for accurate risk prediction. Our goal is to develop and refine a comprehensive, precision “risk signature” that more accurately guides clinical decision-making and identifies the most appropriate pathway to care for each patient. By improving risk stratification and aligning treatment strategies with individual biology and context, this work aims to reduce disparities and advance equity in prostate cancer outcomes.

BMC Cancer Research Innovator (PI: Heaphy)

PROJECT 6. Stromal senescence as a driver of lethal prostate cancer progression. Cellular senescence is a dynamic stress response characterized by durable growth arrest and the acquisition of a pro-inflammatory secretory program known as the senescence-associated secretory phenotype (SASP). In prostate cancer, stromal fibroblasts are highly susceptible to senescence in response to chronic inflammation, oxidative stress, and DNA damage. Senescent stromal fibroblasts actively reshape the tumor microenvironment through secretion of SASP factors that promote cancer cell survival, invasion, angiogenesis, and extracellular matrix remodeling. These changes create a permissive, tumor-promoting niche that facilitates disease progression and therapeutic resistance. Using an integrated patho-epidemiology approach, we are testing the overarching hypothesis that senescent, inflammation-associated stromal fibroblasts drive aggressive and lethal prostate cancer. This work aims to define stromal senescence as a clinically relevant determinant of prostate cancer outcomes and a potential target for intervention.