Current research in the Kurie Laboratory is centered on the investigation of mechanisms of lung cancer metastasis for the purpose of identifying novel therapeutic targets. Of foremost interest is to understand how the cellular and extracellular matrix constituents of the tumor microenvironment are controlled by tumor cells, and how signals from the microenvironment influence tumor cell behavior. In this effort, the Kurie lab uses cellular models, genetic mouse models of lung cancer that recapitulate key somatic genetic mutations and epigenetic events in tumor cells, and a tissue bank of molecularly and clinically annotated human lung cancers and matched normal lung.
Research areas of interest in the laboratory include:
1. Elucidating how somatic mutations in cancer cells activate secretory vesicle biogenesis in the Golgi to drive malignant secretion and metastasis. Heightened secretion of pro-tumorigenic effector proteins is a feature of malignant cells. Yet the molecular underpinnings and therapeutic implications of this feature remain unclear. The Kurie lab identified a chromosome 1q region that is frequently amplified in diverse cancer types and encodes multiple regulators of secretory vesicle biogenesis and trafficking, including the Golgi-dedicated enzyme phosphatidylinositol (PI)-4-kinase IIIβ (PI4KIIIβ). Molecular, biochemical, and cell-biological studies showed that PI4KIIIβ-derived PI-4-phosphate (PI4P) synthesis enhances secretion and accelerates lung adenocarcinoma progression by activating GOLPH3-dependent vesicular release from the Golgi. PI4KIIIβ-dependent secreted factors maintain 1q-amplified cancer cell survival and influence pro-metastatic processes in the tumor microenvironment. Disruption of this functional circuitry in 1q-amplified cancer cells with selective PI4KIIIβ antagonists induces apoptosis and suppresses tumor growth and metastasis. These results support a model in which chromosome 1q amplifications create a unique dependency on PI4KIIIβ-dependent secretion for survival. This project offers the fellow an opportunity to gain expertise in autochthonous lung tumor development, microscopy, cell biology, and biochemistry in a novel field with strong translational potential.
2. Exploring how epithelial-to-mesenchymal transition (EMT) governs tumor cell polarity and metastasis. Metastasis is the primary cause of death in patients with lung cancer, and its genetic and biological bases are poorly understood. Progress in this area has been hampered by the lack of in vivo models that faithfully recapitulate genetic and biochemical features of human lung cancer metastasis. To address this knowledge gap, the Kurie lab has developed a series of genetically-engineered mouse models of human lung adenocarcinoma initiated by K-rasG12D expression in which secondary oncogenic mutations, including Tp53R172H expression or inactivation of Pten or Map2k4, lead to more advanced disease but differ in the degree to which they promote disease advancement. Their transcriptional profiling studies revealed that poor-prognosis human lung adenocarcinomas were highly enriched in genes differentially expressed between primary and metastatic tumors in mice that develop widely metastatic lung adenocarcinomas owing to expression of K-rasG12D and p53R172H (KP mice). They showed that KP mice harbor disease whose progression closely mirrors that of poor-prognosis lung adenocarcinoma in patients and that lung adenocarcinoma cell lines derived from these mice provide a useful platform for the discovery of clinically relevant, pharmacologically actionable metastasis drivers. Metastatic tumor cells derived from KP mice switch reversibly between epithelial and mesenchymal states in response to extracellular cues; this plasticity is critical for metastasis and is driven by mutual antagonism between transcription factors that activate EMT (e.g., ZEB, SNAIL, and TWIST family members) and microRNAs that target the EMT-activating transcription factors (e.g., miR-200 and miR34 family members). They are currently studying how the EMT regulatory axis governs tumor cell polarity and the formation of actin-based cytoplasmic protrusions (e.g., filopodia and lamellipodia) by controlling vesicular trafficking through endocytic recycling, retrograde, and anterograde pathways. This project offers fellows an opportunity to gain expertise in advanced microscopy (point-scanning high-resolution confocal microscopy, spinning disc microscopy, total internal reflection fluorescence), tumor cell biology, and mouse modeling.
3. Elucidating how extracellular signals govern tumor cell metastatic activity. To address this question, the Kurie lab has created murine and cellular models of human lung cancer in which tumor cells and collagenous stroma can be visualized microscopically in 3 dimensions and in real time. They showed that tumor cells gain metastatic properties by inducing the formation of a particularly stable type of collagen cross-link driven by high expression of lysyl hydroxylase 2 (LH2), a collagen lysyl hydroxylase. They also showed that this enzyme is secreted and modifies both intracellular nascent collagen strands and extracellular triple helical collagen molecules, and that LH2-driven cross-links enhance the migratory and invasive properties of tumor cells. They generated the first crystal structure of a collagen lysyl hydroxylase and used that knowledge to identify small molecule inhibitors of LH2 from high throughput screens. This project offers fellows an opportunity to gain expertise in enzymology, collagen biochemistry, and tumor cell biology in a novel field with strong translational potential.
4. Identifying and targeting pro-metastatic cancer-associated fibroblasts (CAFs). CAFs are mesenchymal cells of diverse origins. CAFs exhibit a high degree of intra-tumoral heterogeneity that allows them to execute multiple pro-metastatic functions in the tumor microenvironment. The Kurie lab comprehensively analyzed CAF heterogeneity and its molecular underpinnings in lung adenocarcinoma. Among ~ 80,000 fibroblasts analyzed, heterogeneity was greater in lung adenocarcinoma than it was in idiopathic pulmonary fibrosis, a disease associated with high lung cancer risk from progressive fibrosis. At the single-cell transcriptomic level, CAFs segregated into distinct clusters, 2 of which demonstrated hallmarks of strongly activated fibroblasts and were correlated with shorter survival. In co-culture with lung adenocarcinoma cells, CAFs acquired transcriptomic hallmarks of poor-prognostic clusters, a shift driven by an EMT-dependent secretory program in tumor cells. The capacity of CAFs to enhance metastasis in mice and to generate invasive structures in 3-dimensional collagen gels depended on tumor cell EMT state. Adherence to collagen was a targetable vulnerability in poor-prognostic CAF clusters.