Mechanisms associated with organotropic metastasis

与器官转移相关的机制

• 批准号: 10295926
• 负责人: RAGHU KALLURI
• 金额: $ 51.01万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10295926
• 关键词: Affect; Blood Vessels; Bone Marrow; Breast Carcinoma; Breast cancer metastasis; Cancer Patient; Cells; Cues; Data; Disease; Distant; Endothelial Cells; Endothelium; Environment; Expression Profiling; Extracellular Matrix; Extravasation; Fibroblasts; Fibrosis; Gene Deletion; Genetically Engineered Mouse; Growth; Growth Factor; Heterogeneity; Homing; Immune; Inflammation; Intercellular Junctions; Kidney; Lead; Liver; Lung; Lymphatic; Malignant Neoplasms; Mediating; Mediator of activation protein; Metastatic Neoplasm to the Kidney; Metastatic Neoplasm to the Lung; Molecular; Molecular Profiling; Molecular Target; Mus; Neoplasm Metastasis; Nonmetastatic; Organ; Production; Proteins; Proteomics; Pulmonary Fibrosis; Reporter; Repression; Role; Route; Seeds; Signal Transduction; Soil; Solid Neoplasm; Source; Testing; Therapeutic; Tissues; Tropism; Vascular Endothelial Cell; Vascular Endothelium; Vascular Permeabilities; cancer cell; cell type; cellular targeting; chemokine; cytokine; design; exosome; experimental study; extracellular vesicles; gain of function; insight; kidney fibrosis; lung colonization; malignant breast neoplasm; mouse model; neoplastic cell; new therapeutic target; novel; recruit; single cell analysis; single cell technology; single-cell RNA sequencing; tumor; vascular bed

ABSTRACT Most cancer patients with solid tumors die of metastatic disease and organotropic spread is an understudied aspect of metastasis, for which new insights are urgently required. The prevailing ‘seed and soil’ concept posits that permissive environment in a distant organ (soil) is necessary to support the survival and growth of lurking tumor cells (seeds). Induction of permissive soil in a non-metastatic organ is proposed to re-route metastasis; however, rigorous experimental evidence and mechanistic analyses are lacking. Fibrotic tissue alterations, including inflammation, provide cues for metastasis, together with the signals from bone marrow-derived cells (BMDCs), the tumor secretome, and circulating extracellular vesicles. Our preliminary data suggest organotropic metastasis is not solely dependent on permissive matrix remodeling and BMDCs in the secondary organs, but is also contingent on the disruption of vascular endothelial barrier function imposed by organ-specific vascular junction proteins. Our findings lead to a central hypothesis that ‘vascular heterogeneity functionally contributes to organotropism of metastasis’. We propose studies to unravel the mechanisms, by which distinct fibrotic niches effect organ-specific changes in the vascular beds, leading to organotropic metastasis. Preliminary studies identified angiopoetin-2 (Ang-2) as a putative mediator of lung metastasis. We aim to unravel the mechanisms of Ang-2 dependent tropism to the lung but not the kidney or liver, which also generate high Ang-2 levels in the fibrotic setting. Using single-cell RNAseq and CyTOF, we will determine the cellular and molecular targets of Ang-2 in the pre-metastatic milieu. Preliminary studies show Ang-2 induces vascular leakage in the lung vasculature without impacting kidney or liver vessels, thus directing metastasis to the lung. Exosomes released by the fibrotic organs also increase vascular permeability and metastatic colonization in the lung, without affecting kidney or liver vasculature. Single-cell RNAseq of fibrotic organs, as well as genetically engineered mice (GEMs), will be used to unravel the rate limiting effect of tissue-specific disruption of Ang-2 in breast cancer metastasis. Using novel GEMs generated in the lab, we will trace lineage-specific production of metastasis- inducing exosomes and identify the determinants of organotropism via proteomic analysis. Our preliminary studies show Ang-2 disrupts vascular barriers through repression of claudin-5 that is found exclusively in the lung vasculature, in contrast with the kidney and liver vessels, which present with multiple, redundant endothelial claudins. Integrating mouse models with endothelial-specific deletion of claudin-5 and claudin-5 reporter mice, and with molecular profiling of organ-specific endothelial cells in loss- and gain-of-function experiments, we will elucidate functions of specific claudins in organotropic metastasis. Molecular studies will be performed to identify putative mechanism of Ang-2 mediated suppression of claudin-5 and test whether manipulation of vascular permeability can re-route metastasis regardless of cancer-specific organ predilection. Successful completion of the proposed studies will provide new insights into mechanism of metastasis and therapeutic implications.

摘要