Interrogating drivers of plasticity in early lung cancer tumorigenesis and metastatic dormancy.

PROJECT SUMMARY/ABSTRACT Cancer is often diagnosed at advanced stages when tumors are highly heterogeneous, aggressive, and have metastasized, limiting the effectiveness of current therapies and leading to patient relapse. This is particularly true of lung adenocarcinoma (LUAD), which accounts for 7% of global cancer mortality. Targeting early, less heterogeneous lung neoplasias could offer curative potential, yet the mechanisms driving early tumorigenesis in vivo are poorly understood. Notably, plasticity—the ability of cancer cells to undergo state transitions via non-genetic mechanisms—plays a critical role in cancer initiation, progression, metastasis, and therapy resistance. Recent work in our lab identified a highly plastic cell state (HPCS) in primary LUAD tumors that drives tumor heterogeneity and therapy resistance. Understanding the drivers of phenotypic plasticity during early tumor progression and metastatic dormancy is essential for developing strategies to intercept early tumorigenesis and prevent the outgrowth of disseminated tumor cells, ultimately improving patient outcomes. My predoctoral research (Aim 1) focuses on identifying the molecular mechanisms driving plasticity in early lung cancer tumorigenesis in vivo. A focused in vivo CRISPR screen targeting genes specifically expressed in HPCS cells revealed several candidates, including uPAR and EPCR, as drivers of early LUAD tumorigenesis. Therefore, the objective of Aim 1 is to validate uPAR and EPCR as drivers of phenotypic plasticity in HPCS cells and investigate the underlying molecular mechanisms during early tumor progression. Targeting these early mechanisms could lead to effective new therapies for preventing lung cancer in high-risk individuals. My postdoctoral research (Aim 2) will focus on exploring the regulators of metastatic dormancy using a spontaneous metastasis mouse model. ScRNA-sequencing and spatial transcriptomics will identify candidate transcriptional programs and cellular neighborhoods linked to dormancy. Aim 2 seeks to uncover molecular mechanisms that drive phenotypic plasticity and metastatic outgrowth from dormant cells, using genetic and in vivo imaging tools to elucidate and validate key regulatory mechanisms. The overarching hypothesis is that targeting plasticity in disseminated tumor cells can inhibit their transition to overt macrometastases. Together, these two aims lay the foundation for developing therapies targeting plasticity, with the potential to improve outcomes for patients at high risk of developing lung cancer and those with existing advanced metastatic disease. Furthermore, our findings could extend beyond LUAD, offering insights applicable to other cancer types characterized by phenotypic plasticity and metastasis. This research will be conducted in Dr. Tuomas Tammela’s laboratory at Memorial Sloan Kettering Cancer Center (MSKCC), one of the world's leading cancer research and treatment institutions. The state-of-the-art resources and collaborative environment at MSKCC, along with support from the Gerstner Sloan Kettering Graduate School, offer an ideal setting to ensure the successful completion of my research and career development goals.