Overview
Our laboratory is focused on dissecting the complex and dynamic interactions between tumors and their surrounding microenvironment, with a central aim of understanding the mechanisms that fuel tumor progression and resistance to therapy. We approach this challenge through three major research themes: (i) the role of cancer plasticity in tumor evolution and adaptation, (ii) the contribution of stromal fibroblasts to therapeutic resistance and immune evasion, and (iii) the emerging intersection of osteoimmunology and cancer biology. Our work seeks to uncover both tumor-intrinsic and microenvironmental drivers of disease progression by integrating cutting-edge technologies, including single-cell and spatial genomics, ex vivo organoid systems, and in vivo models that closely mirror human prostate and renal cell carcinomas.
These platforms enable us to interrogate the functional relevance of key pathways and cellular interactions in a controlled yet biologically meaningful context. To maintain clinical relevance, we rigorously validate our discoveries using large-scale human single-cell datasets and patient-derived tumoroid models. This translational approach allows us to bridge basic mechanistic insights with potential therapeutic applications. Ultimately, our mission is to identify novel, targetable vulnerabilities within the tumor ecosystem and advance strategies that improve outcomes for patients facing advanced cancer.
Research Areas
Cancer Plasticity
Cancer plasticity remains a formidable barrier to durable treatment responses across virtually all solid tumors. In collaborative work, we identified the JAK/STAT signaling axis as a central driver of lineage plasticity and therapeutic resistance in prostate cancer (PMID 35981096 and PMID 38645034). Using sophisticated preclinical prostate cancer models, we have been able to modulate sensitivity to androgen receptor signaling inhibitors (ARSIs), uncovering a critical vulnerability that led to a multicenter Phase 1b/2 clinical trial evaluating the combination of JAK/STAT and ARSI inhibition. Building on these findings, our current efforts aim to delineate how JAK/STAT signaling interacts with other oncogenic pathways to sustain plasticity and therapy resistance. To achieve this, we employ CRISPR-based functional genomic screens alongside integrative computational analyses across both human tumor datasets and mouse models. We also leverage high-resolution single-cell technologies to analyze patient-derived samples, with the goal of identifying additional key regulators and cellular states that contribute to tumor adaptation and drug resistance. Ultimately, our research seeks to unravel the complex signaling crosstalk underlying plasticity and translate these insights into rational, mechanism-based therapeutic strategies.
Tumor Stroma
The tumor microenvironment plays a pivotal role in shaping therapeutic response, with immune cells and fibroblasts acting as key modulators of resistance. Our recent work (PMID 38645034) has uncovered two critical cellular components within the tumor stroma that contribute to prostate cancer resistance. These discoveries further underscore the importance of the dynamic crosstalk between tumor cells and their stromal contexts. Moving forward, we will utilize advanced in vivo models to dissect the functional relevance of these components in driving resistance and antitumor immunity. By integrating these experimental approaches with comprehensive analyses of patient-derived tissues and immunogenomic datasets, we aim to validate the translational significance of our findings. Our ultimate goal is to define actionable targets within the tumor stroma that can be leveraged to overcome resistance and enhance treatment durability.
Osteoimmunology
Bone is a frequent and clinically significant site of metastasis across multiple cancer types, particularly in advanced prostate cancer. Metastatic spread to the bone is often associated with substantial morbidity and limited therapeutic options. Our research focuses on identifying and characterizing the key molecular and cellular events that enable tumor cells to colonize the bone microenvironment. Specifically, we investigate the formation of pre-metastatic niches—pro-tumorigenic changes in the bone stroma that precede overt metastasis—and the role of tumor-secreted and bone-derived factors such as osteokines in promoting metastatic seeding and outgrowth (PMID 38718755). In parallel, we examine the bidirectional communication between bone-resident cells (such as osteoblasts, osteoclasts, and stromal components) and metastatic tumor cells. This includes studying how these interactions influence not only tumor proliferation and survival but also the remodeling of local immune landscapes and the induction of systemic immunological changes that may contribute to immune escape or resistance to therapy. Through a combination of in vivo bone metastasis models, molecular profiling, and human tissue analyses, our goal is to uncover new therapeutic vulnerabilities in the bone-tumor-immune axis and ultimately improve outcomes for patients with skeletal metastatic disease.
