Our research builds on the foundation of tumor-microenvironment interaction, with emphasis on elucidating the factors and signaling pathways driving cancer plasticity, cancer local invasion, and distant metastasis. We have built relevant cancer cell lines and models closely mimicking human cancer progression to study racial disparities in clinical prostate cancer specimens, to understand the developmental aspects of genitourinary cancers, and to identify crucial cell signaling networks that are druggable for improved treatment of cancer metastasis. To achieve our goals, we develop novel technologies, cell lines and models, and new concepts to pursue a fundamental understanding of the metastatic progression of cancer cells and their ability to develop therapeutic resistance. We collaborate with both clinical and basic science investigators to seek opportunities to validate our concepts and hypotheses in clinically relevant specimens. A list of representative laboratory projects includes:
Three dimensional (3-D) reconstruction of tissues and cells to identify the molecular mechanisms underlying tumor-stromal interaction promoting prostate cancer progression
3-D culture of prostate cancer cells was selected by NASA for scientific exploration in 2003. From the failed shuttle Columbia flight, we observed evidence of enhanced cancer-matrix interaction with prostate cancer cells forming golf ball-size tumor aggregates in space when compared to the same 3-D culture under microgravity simulated growth conditions on the ground.
Coevolution of cancer and stroma during cancer progression
Coevolution of prostate cancer and stromal cells has been observed upon cellular interaction under 3-D co-culture conditions.Permanent genomic and epigenomic modifications have been documented. In addition, a novel cell fusion mechanism involving a prostate cancer epithelial cell (tagged with RFP, red fluorescence protein) and bone marrow stem cells (tagged with GFP, green fluorescence protein) yielded a hybrid fused cell, as shown in yellow.
Cancer plasticity through epithelial to mesenchymal transition and the ability of cancer cells to assume stem cell and neuroendocrine (NE) properties are studied to understand cancer invasion and metastasis. We identified the presence of "cancer metastasis initiating cells," which recruit bystander cancer cells to form tumors in mouse skeleton and soft tissues
Under the influence of autocrine/paracrine RANKL-RANK signaling, we observed dynamic plasticity including EMT, stemness, and neuroendocrine differentiation of prostate cancer cells. Potential recruitment of bystander prostate cancer cells by "metastasis-initiating cell" to form bone and soft tissue metastases was observed.
Near-infrared fluorescent dye for cancer diagnosis and treatment
A novel near-infrared organic fluorophore was identified with selectivity for both localized and disseminated cancers. These organic dyes enter cancer cells through organic anion transport peptides. They can be further chemically modified to generate selective agents for improved imaging and targeting of metastatic cancers.
Technology development and improvements in the detection of circulating tumor cells, single cell genome sequencing, and multiplex quantum dot fluorescent imaging
Multiplex quantum dot imaging of primary prostate cancer from patients revealed the presence of either fully (M) or partially mesenchymal transitioned epithelial cells (E/M), at a single cell level, toward expression of the mesenchymal phenotype.
Novel therapeutic targeting of cancer cells and their associated stroma
Novel strategies developed by our laboratory co-target cancer and bone cells using genetic therapy or targeting the interface between cytokine, chemokine, and extracellular matrices and their receptors. Our work focuses on osteomimicry-based targeting plus RANKL-RANK signaling and its convergent c-Met signaling.