Targeting cooperative mechanisms of metastatic colonization in osteosarcoma

骨肉瘤转移定植的靶向合作机制

• 批准号: 10366421
• 负责人: RYAN D. ROBERTS
• 金额: $ 65.29万
• 依托单位: RESEARCH INST NATIONWIDE CHILDREN'S HOSP
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-06 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10366421
• 关键词: Adopted; Aftercare; Antibodies; Appearance; Automobile Driving; Bar Codes; Behavior; Biology; Cell Communication; Cell Survival; Cell division; Cells; Characteristics; Child; Childhood; Clinical; Data; Data Set; Development; Developmental Process; Disease; Disease Resistance; Drug Targeting; Environment; Epithelial Cells; Exposure to; Extracellular Matrix; Frequencies; Genetic Transcription; Growth; Human; IL6 gene; IL8 gene; In Vitro; Individual; Inflammatory; Integrins; Interleukin-1; Intervention; Laboratories; Lesion; Lung; Lung Neoplasms; Maintenance; Malignant Bone Neoplasm; Metastatic Neoplasm to the Lung; Mus; Neoplasm Metastasis; Nodule; Organoids; Patient Care; Persons; Pharmacology; Phenotype; Play; Population; Positioning Attribute; Primary Neoplasm; Production; Proliferating; Property; Reaction; Regimen; Relapse; Reporter; Research; Resistance; Resolution; Role; Signal Transduction; Stress; Structure of parenchyma of lung; System; Teenagers; Testing; Therapeutic Intervention; Time; Tissues; Toxic effect; Translating; Treatment Protocols; Work; cancer cell; cell growth; cell type; cellular engineering; chemotherapy; clinical care; conventional therapy; cytokine; healing; improved outcome; in vivo Model; inhibitor; mouse model; neoplastic cell; novel; osteosarcoma; paracrine; preference; prevent; recruit; response; single-cell RNA sequencing; standard of care; targeted treatment; therapeutic candidate; therapeutic development; therapy design; tumor; wound; wound healing; wound response

While studying mechanisms of metastasis in osteosarcoma, we discovered that individual tumor cells respond differently when exposed to the foreign lung environment. Our early data suggest a hypothesis: that a small group of tumor cells survives the initial encounter with the lungs by stopping cell division and liberally producing inflammatory cytokines. The reaction of these rare “anchor” cells changes the surrounding lung tissue in ways that prepare it for colonization by rapidly proliferating tumor cells (“growth” cells). The cytokines released by anchor cells appear to alter the behavior of the surrounding lung cells, prompting a wound healing response. Unlike the normal wound healing response, however, this wound never heals. The environment created by this wound response is markedly different from that of the normal, healthy lung. Most importantly, cells and cytokines that make up the wound create an environment where growth cells not only survive, but proliferate rapidly, outcompeting the anchor cells to become the dominant subtype within the metastatic tumor. Here, we outline a research plan to test this hypothesis, rigorously evaluating our proposed mechanisms that establish the early metastatic niche and asking whether chemotherapy selectively kills growth cells, inadvertently leaving anchor cells intact to re-establish metastases once therapy ceases. The project is divided into three Aims. Aim 1 tests hypotheses relating to the mechanisms by which anchor cells create a fertile metastatic niche by activating the wound-healing machinery of the lung and facilitates identification of the lung-to-tumor signals that make this a fertile environment for growth cells. In the second Aim, we will determine how anchor and growth cells come about—whether distinct clones come pre-programmed for anchor or growth cell activity or whether dynamic developmental processes regulate maintenance of subpopulations within each tumor. Understanding this will be important for designing treatment regimens that maintain efficacy while minimizing toxicity. Finally, we will evaluate the use of pharmacologic inhibitors that target anchor cells directly or indirectly to see if these can augment the effects of conventional therapies and overcome resistance and relapse. By identifying agents that selectively target anchor cells, we can develop combination regimens that target both groups of tumor cells, rendering resistant disease treatable. The cooperation between cancer cells with discrete behaviors has immediate implications for treatment and suggests a need to develop strategies that target both growth cells and anchor cells. This work could drive a paradigm shift that would revolutionize the care of patients with osteosarcoma.

在研究骨肉瘤的转移机制时，我们发现单个肿瘤细胞有应答