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Project 2: Effect of HTLV-1 Viral Oncogenes on the Bone Microenvironment during tumor growth and progression in ATL

项目2：HTLV-1病毒癌基因对ATL肿瘤生长和进展过程中骨微环境的影响

基本信息

批准号：
10632070
负责人：
DEBORAH J VEIS
金额：
$ 42.95万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-04-21 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10632070
关键词：
Ablation Active Sites Adult Adult T-Cell Leukemia/Lymphoma Affect Animals Biological Availability Biological Models Blood Cells Bone Diseases Bone Resorption Bone neoplasms CRISPR/Cas technology Cancer Model Cell Communication Cell Line Cell surface Cells Collaborations Data Development Environment Experimental Designs Extracellular Matrix Funding Growth Factor HTLV-1 Infection Heparitin Sulfate Human Human T-lymphotropic virus 1 Hypercalcemia Immune response Immune system Immunodeficient Mouse Implant In Vitro Individual Infection Injections Lesion Lymphoma cell Lymphoproliferative Disorders Lytic Metastatic Lesion Malignant Neoplasms Malignant neoplasm of prostate Marrow Mediating Mediator Modeling Multiple Myeloma Mus Oncogenes Osteoblasts Osteoclasts Osteolytic Pathogenesis Pathologic Patients Persons Phenotype Play Process Productivity Protein Isoforms Proteins Recurrence Reporting Resistance Retroviridae Role T-Lymphocyte TNFSF11 gene Taxes Techniques Therapeutic Transgenic Mice Transplantation Tumor-Derived Umbilical Cord Blood Viral Viral Oncogene Viral Vector WNT Signaling Pathway Work analysis pipeline antagonist bone bone cell bone invasion bone loss chemotherapy cytokine experience experimental study heparanase humanized mouse implantation in vivo in vivo Model intraperitoneal leukemia malignant breast neoplasm mouse model mutant paracrine patient derived xenograft model pharmacologic pleiotropism programs success three dimensional cell culture tumor tumor growth tumor microenvironment tumor progression tumorigenesis tumorigenic vector

项目摘要

PROJECT SUMMARY – PROJECT 2 Adult T-cell leukemia/lymphoma (ATL) develops in a subset of people infected with HTLV-1 and is an aggressive T-cell malignancy. ATL’s unique relationship to bone (long latency in the marrow, bone invasion, osteolytic lesions, and hypercalcemia) makes it an ideal model to dissect the critical factors that support tumor development and progression in bone. Thus, our work on ATL will likely shed light on other late recurring and bone-tropic tumors like multiple myeloma, breast, and prostate cancer. Using transgenic mice, we showed that the HTLV-1 tax viral oncogene can mediate both ATL development as well as osteolytic bone destruction through effects on bone-resorbing osteoclasts (OCs). However, Tax expression is downregulated in ~70% of human ATL, despite ongoing bone involvement and bone loss, suggesting that another viral factor is important. Recently, we found that HBZ, a second HTLV-1 oncogene, can also lead to lymphoproliferative disease and pathologic bone loss when expressed transgenically or in a humanized mouse model of HTLV-1 infection. RANKL plays an important role in this process, but is not a direct target of HBZ. We and others find that HBZ upregulates the expression of Wnt5a and heparanase (HPSE), tumor-derived paracrine factors that modulate the tumor microenvironment in bone and are upregulated in patient ATL cells. Wnt5a activates noncanonical Wnt signaling via Ror2 and has both osteoblast-inhibiting and OC-stimulating activities, including increasing RANKL expression. HPSE enzymatically cleaves heparan sulfate, thereby altering cell surfaces and extracellular matrix, increasing bioavailability of growth factors and cytokines including RANKL and likely Wnt5a. We hypothesize that hbz expression in transformed ATL cells reprograms the bone microenvironment via increasing Wnt5a and Heparanase expression, and thereby affects tumor progression and bone loss. Our plan for evaluating this hypothesis relies integrally on the in vivo models that were developed during the previous funding period, including new patient-derived xenograft (PDX) models that cause systemic bone loss in mice following intraperitoneal (IP) implantation and newly characterized local bone effects of established ATL cell lines following implantation into bone (with intratibial injection; IT). We will make extensive use of viral vectors to manipulate Wnt5a and HPSE in these ATL and PDX lines, primarily with CRISPR/Cas9, taking advantage of the expertise of Dr. Yoder (Vector Core 1). In collaboration with Dr. Niewiesk (Animal Core 2), we have also implemented a humanized immune system (HIS) model in which immunodeficient mice are transplanted with human cord blood cells, and then infected with HTLV-1, modeling emergence of lymphoproliferative disease (LPD) accompanied by systemic bone loss. This collaboration will be a key part of our experimental design.

项目总结-项目2