Lethal bone metastasis frequently develops in patients with castration-resistant prostate cancer (CRPC). Critically, the biology of this conditio remains uncertain. Our currently funded Program Project Grant (PPG) focuses on characterizing selected soluble factors, heparan sulfate proteoglycans (HSPG) and reactive oxygen species (ROS) secreted by cancer cells and cells in the tumor microenvironment, to develop biomarkers to predict PC progression and treatment response. Our progress during the current funding period includes several patents and the development of multiple antibodies recognizing HSPG fragments for potential commercialization as diagnostic/ prognostic biomarkers. We also humanized a therapeutic antibody against ?2-microglobulin for clinical translation to treat PC bone metastasis. In this competitive renewal application, our long-term redefined goal is to pursue new concepts in the tumor microenvironment that redirect tumor cells toward a metastatic phenotype. These innovations include the discoveries that (1) metastasis can be coordinated by Metastasis Initiating Cells (MICs) (Project 1: Chung), (2) the HSPG perlecan and its degradative products are critical mediators of PC metastasis (Project 2: Farach-Carson); (3) cells with megakaryocyte and/or osteomimetic (MO-mimicry) properties reside in primary tumors and can be altered by stromal factors to metastasize to bone (Project 3: Bhowmick); and (4) epigenetic programming of the PC genome can affect cholesterol and sterol metabolism in a manner that promotes metastasis (Project 4: Freeman). To test these concepts, we will use approaches and resources unique to our team. We showed that MICs can reprogram non-metastatic dormant cells through a feed-forward action involving a RANK-mediated signaling network, provoking them to participate in bone colonization. This novel concept is supported by substantial data from animal models and a unique population of hormone-nave PC patients with bone metastasis and pathologic specimens collected from patients with known overall survival. We will pursue the underlying biology of how circulating tumor cells (CTCs) and disseminated tumor cells (DTCs) (Project 1- Chung), and endothelial and inflammatory cells (Project 2), are recruited to participate in the metastatic cascade. We propose to develop biomarkers to predict which patients will switch from indolent to aggressive disease. Our long range objectives will be achieved by identifying signaling pathways converging on critical nodes that can be targeted with drugs. Our team has developed a range of state-of-the-art methods and tools, including single cell methods of tumor cell isolation using NanoVelcro microfluidics, whole genome sequencing, quantitative IHC by multiplex quantum dot labeling (mQDL), ChIP-seq and RNA-seq analyses. We have demonstrated success in 3D culture of human DTCs, tissue recombinants comprised of engineered human and murine cells, and reliable models of human PC bone and soft tissue metastases.
Cancer metastasis is a highly inefficient process. Our team has discovered several new mechanisms that suggest that the fate of a dormant cell population can be tipped toward metastasis. These influences arise from the tumor microenvironment, and include perturbations of inflammatory and stem cell renewal pathways, cell-cell interaction, protein stability and disruption, and metabolism.
|Rohena-Rivera, Krizia; Bhowmick, Neil A (2018) Notch inhibitor screening reveals an unexpected HES1 heterodimer. J Biol Chem 293:8295-8296|
|Tighiouart, Mourad; Cook-Wiens, Galen; Rogatko, André (2018) A Bayesian adaptive design for cancer phase I trials using a flexible range of doses. J Biopharm Stat 28:562-574|
|Madhav, Anisha; Andres, Allen; Duong, Frank et al. (2018) Antagonizing CD105 enhances radiation sensitivity in prostate cancer. Oncogene 37:4385-4397|
|Jan, Yu Jen; Chen, Jie-Fu; Zhu, Yazhen et al. (2018) NanoVelcro rare-cell assays for detection and characterization of circulating tumor cells. Adv Drug Deliv Rev 125:78-93|
|Grindel, Brian J; Martinez, Jerahme R; Tellman, Tristen V et al. (2018) Matrilysin/MMP-7 Cleavage of Perlecan/HSPG2 Complexed with Semaphorin 3A Supports FAK-Mediated Stromal Invasion by Prostate Cancer Cells. Sci Rep 8:7262|
|Jimenez, Jose L; Tighiouart, Mourad; Gasparini, Mauro (2018) Cancer phase I trial design using drug combinations when a fraction of dose limiting toxicities is attributable to one or more agents. Biom J :|
|Martinez, Jerahme R; Grindel, Brian J; Hubka, Kelsea M et al. (2018) Perlecan/HSPG2: Signaling role of domain IV in chondrocyte clustering with implications for Schwartz-Jampel Syndrome. J Cell Biochem :|
|Farach-Carson, Mary C; Lin, Sue-Hwa; Nalty, Theresa et al. (2017) Sex Differences and Bone Metastases of Breast, Lung, and Prostate Cancers: Do Bone Homing Cancers Favor Feminized Bone Marrow? Front Oncol 7:163|
|Stewart, Paul A; Khamis, Zahraa I; Zhau, Haiyen E et al. (2017) Upregulation of minichromosome maintenance complex component 3 during epithelial-to-mesenchymal transition in human prostate cancer. Oncotarget 8:39209-39217|
|Nandana, Srinivas; Tripathi, Manisha; Duan, Peng et al. (2017) Bone Metastasis of Prostate Cancer Can Be Therapeutically Targeted at the TBX2-WNT Signaling Axis. Cancer Res 77:1331-1344|
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