The role of the lymphatic niche in stem cell plasticity and tumor progression in skin cancer

About This Grant

PROJECT SUMMARY/ABSTRACT Squamous cell carcinoma (SCC) is one of the most common cancers worldwide, yet the early events that drive mutated epithelial stem cells toward malignancy remain poorly understood. While cellular plasticity has emerged as a key process enabling clinically normal mutation-harboring skin to acquire oncogenic potential and undergo malignant transformation, the non-genetic variables that regulate this process and ultimately drive tumorigenesis remain largely unknown. These gaps in knowledge can largely be attributed to a dearth of tools and models that capture pre-oncogenic stem cell identity landscape in intact tissues. In this project, I will investigate how the lymphatic vascular niche, increasingly recognized as a key regulator of epithelial stem cell, controls cancer stem cell fate transitions during early tumor initiation and malignant progression in skin SCC. Using deep imaging and sequencing approaches, we discovered that lymphatic vascular insufficiency predisposes stem cells to malignant transformation, while oncogenic plasticity propelling the transition from benign to metastatic carcinoma is preceded by dynamic lymphatic remodeling. The central hypothesis is that lymphatic niches evolve during tumor progression, initially supporting tolerance to oncogenic stress and later driving epigenetic rewiring that enables malignant transformation. Aim 1 will determine how lymphatic regression influences tolerance to oncogenic stress and promotes malignant transformation using in vivo lymphatic ablation models, chromatin accessibility profiling and organotypic culture systems. Aim 2 will define the molecular and spatial interactions between tumor-initiating cells and lymphatic niches during malignant progression. Leveraging enhancer-based proximity sensors, I will identify lymphatic-derived signals that promote stem cell plasticity potential. This work is expected to reveal context-dependent lymphatic cues that regulate early tumor initiation and malignant transition, while generating new tools to study vascular–stem cell interactions in vivo. These studies aim to uncover actionable pathways that can be targeted to intercept skin cancer before it becomes invasive, offering new opportunities for early intervention in a disease that affects millions. My training will take place in the Gur-Cohen Lab at UC San Diego and the Sanford Stem Cell Institute, a highly interdisciplinary environment with access to state-of-the-art tools in imaging, genomics, and computational biology. In this fellowship, I will gain advanced expertise in 3-dimensional tumor imaging, epigenomic analysis, and the development of experimental tools to interrogate the cancer stem cell interactome in real time. Under the guidance of a dedicated mentoring team, I will also strengthen my skills in scientific communication, grant writing, and mentorship. This integrated research and training plan will prepare me for an independent academic career focused on understanding how systemic signals influence stem cell fate and oncogenic potential.