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Current Research

During mammalian development, cells with otherwise identical genomes use dynamic gene expression programs to generate diverse and highly specialized cell types. These tightly regulated transitions are essential for normal tissue formation and function. In diseases such as cancer, however, the mechanisms that govern cellular identity become disrupted by oncogenic mutations that drive uncontrolled growth and survival. A hallmark of tumor progression is lineage plasticity. Unlike the orderly and reversible transitions observed during normal development, cancer-associated plasticity arises from aberrant epigenetic and transcriptional reprogramming and enables tumors to adapt to changing selective pressures.

Lineage plastic tumor cells evade therapy by engaging new developmental programs that bypass the oncogenic dependencies of the original disease. Yet how cancer cells escape lineage constraints to access distantly related identities remains poorly understood. This challenge is exemplified in prostate and lung cancers, where treatment resistance can culminate in neuroendocrine prostate cancer (NEPC) or small cell lung cancer (SCLC) — aggressive disease states that are histologically and molecularly distinct from the adenocarcinomas from which they arise. Why only a subset of tumors undergoes this profound reprogramming, while others remain lineage-restricted, remains a central unresolved question.

Our laboratory seeks to define the molecular rules that govern lineage plasticity in cancer, with a particular focus on how loss of tumor suppressors destabilizes cell identity in both prostate and lung cancer. We study how disruptions in chromatin regulation and transcriptional control in prostate cancer allow tumor cells to explore alternative lineage states, ultimately driving therapy resistance and progression toward NEPC, a highly aggressive and drug-recalcitrant disease state. Central to our research are experimental systems that allow cancer evolution to be studied as a dynamic, time-resolved process rather than a static endpoint.

We develop genetically engineered mouse models (GEMMs) and organoid platforms in which genetic and epigenetic alterations can be introduced, reversed or combined in a controlled manner, enabling direct interrogation of how cell identity and microenvironmental interactions change during tumor progression. By integrating these models with longitudinal analyses and high-resolution molecular profiling, we uncover the spatiotemporal principles that govern tumor progression into alternative cellular states. Ultimately, our work aims to identify vulnerabilities unique to plastic tumor states that can be therapeutically exploited.

RB1 as a Gatekeeper of Tumor Cell Identity:

How does RB1 preserve cell identity and prevent tumor cells from accessing alternative lineage states?

Loss of RB1 is a defining event in aggressive, therapy-resistant prostate cancers, including neuroendocrine prostate cancer. While RB1 is classically known for its role in cell-cycle regulation, emerging evidence from our lab and others demonstrates that RB1 plays a central role in maintaining lineage fidelity. Our lab investigates how RB1 suppresses lineage plasticity. Using inducible genetic models and temporal perturbations, we define how RB1 loss alters chromatin accessibility, transcription factor activity, and cell-state trajectories during tumor evolution. These studies aim to uncover the molecular mechanisms by which RB1 constrains aberrant differentiation programs and prevents malignant cell-state transitions.

Live cell-cycle state tracking in engineered organoids using a Rosa26 FUCCI reporter uncovers how loss of Rb1 and Trp53 rewires proliferative dynamics. G1 (mCherry) and S/G2 (mVenus) populations are visualized and quantified across conditions, revealing genotype-dependent shifts in cell-cycle state distributions.

From organoid to tumor, RPM models reconstruct the histological complexity and lineage plasticity observed in human prostate cancers.

Dynamics and Timing of Lineage Plasticity:

Which genes causally drive lineage plasticity, and which represent actionable vulnerabilities in cancer?

Lineage plasticity is not a binary switch but a dynamic, time-dependent process. Our laboratory develops experimental systems that allow precise control over when genetic lesions are introduced during tumor progression, enabling us to study how the timing of oncogenic events influences cell fate decisions. By combining lineage tracing, single-cell transcriptomics and spatial profiling, we map how tumors traverse intermediate cell states enroute to aggressive phenotypes. These approaches allow us to distinguish reversible adaptive states from irreversible lineage commitments, providing a framework for identifying therapeutic windows in which plasticity can be intercepted.

Interrogation of niche dynamics during histological transformation:

How do tumor cell lineages and their microenvironment co-evolve to enable and sustain lineage plasticity?

Plastic tumor states are accompanied by profound changes in the tumor microenvironment. Our work explores how lineage transitions reshape niche composition and function, with a particular focus on fibroblast and myeloid cell interactions in prostate cancers undergoing histological transformation from adenocarcinoma to neuroendocrine prostate cancer (NEPC). A key advance in our laboratory is the integration of lineage tracing with spatial transcriptomic readouts, enabling us to visualize phylogenetically related tumor clones in their native tissue context. These approaches allow us to define how distinct tumor lineages emerge, expand and organize within the tumor, and to directly observe how tumor cell states influence — and are influenced by — their surrounding niche.

Building on this framework, we combine spatial lineage tracing with multiplexed imaging and pooled functional perturbation strategies to move beyond correlation and establish causality. By systematically perturbing candidate regulators in vivo, we aim to construct a high-resolution interactome of lineage plasticity that defines how tumor-intrinsic programs and microenvironmental signals cooperate to prime, sustain or restrict specific cell states during tumor progression. A major goal of this work is to determine whether targeting plastic tumor states can re-enable productive anti-tumor immune responses and improve responses to immunotherapy.