ccRCC Metastatic Competency Determinants

ccRCC 转移能力决定因素

基本信息

批准号：
10683925
负责人：
Srinivas Malladi
金额：
$ 39.68万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-15 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10683925
关键词：
Address Attenuated Automobile Driving Biological Models Blood Vessels Blood capillaries CXCL1 gene Cancer Patient Cell secretion Cells Cessation of life Chromatin Classification Clear cell renal cell carcinoma Clinical Clinical Management Competence Data Diagnosis Diagnostic Neoplasm Staging Disease Disease Management Distal EPHA2 gene Enrollment Eph Family Receptors Excision Experimental Models Family Family member Genes Genetic Transcription Genomic Segment Growth Histologic Homeobox IL8RB gene Image Immediate-Early Genes Immune Immunologic Surveillance Infiltration Innovative Therapy Invaded Kidney Neoplasms Knowledge Ligands Lymphatic MRI Scans Macrophage Mediating Microscopic Modeling Myelogenous Myeloid Cells Neoplasm Metastasis Nephrectomy Nonmetastatic Operative Surgical Procedures Organ Organoids Patients Peer Review Phosphotransferases Primary Neoplasm Regimen Renal carcinoma Resected Residual Neoplasm Role Signal Transduction Structure Survival Rate Therapeutic Thrombus Transcription Factor AP-1 Transforming Growth Factor beta Tumor Promotion Work X-Ray Computed Tomography antagonist cancer cell cancer genomics chemokine clinical practice cytokine epithelial to mesenchymal transition follow-up genetic manipulation immune cell infiltrate improved in vivo Model inhibitor migration mimicry neoplastic cell neutrophil nuclease patient derived xenograft model pharmacologic programs prospective receptor recruit response single cell sequencing standard of care survival outcome trait transcription factor transcriptomics tumor tumor heterogeneity

项目摘要

Metastatic disease, or the spread of cancer cells from invasive primary tumor to distal organs through vasculature or lymphatics is responsible for majority of patient deaths and remains a clinical challenge. Not all invasive tumors are metastatic, therefore defining the determinants of metastatic competence and identifying cancer patients likely to develop metastasis or have residual disease is critical for clinical management of disease. Intratumor heterogeneity, inability to precisely isolate tumor cells from the invasive front and limited access to clinical follow- up data present a major challenge to identify metastatic competency determinants. Invasive intravascular growth is observed in approximately 15% of ccRCC patients as tumor thrombus. This invasive tumor extension can be accurately identified using cross sectional imaging including computerized tomography and magnetic resonance imaging scans and is valuable for tumor staging. We investigated resected invasive primary tumors with clearly defined extension into the vasculature to identify ccRCC invasion and metastasis determinants. Approximately fifty percent of ccRCC patients with intravascular tumor extension develop metastasis post nephrectomy and treatment and have poor survival outcome. Comprehensive transcriptomic analysis of metastatic and non-metastatic invasive ccRCC tumors with intravascular extension identified metastatic competence determinants. Our central hypothesis is that metastatic competence of invasive ccRCC tumors is dependent on PRRX1 driven vasculogenic mimicry and the ability of chemotactic cytokines to recruit CXCR2 positive infiltrating immune cells to the invasive front that promote dissemination and colonization to distal organs. Pharmacologic and conditional genetic manipulation of PRRX1 and CXCL1 ligands in experimental model systems resulted in attenuated metastasis. We will investigate the role of PRRX1 mediated vasculogenic mimicry in driving metastasis and assess the impact of TGF-β inhibitor on metastatic progression. We will also elucidate the role of CXCL1 in driving metastasis and assess the impact of CXCR2 antagonist on metastatic progression. We anticipate this project will decipher pathophysiologic mechanisms determining metastatic competency of invasive ccRCC and develop innovative therapies to disrupt metastatic competence, which in combination with current standard of care regimens will result in effective management of metastatic disease.

转移性疾病，或癌细胞通过脉管系统从侵袭性原发肿瘤扩散到远端器官或淋巴管是导致大多数患者死亡的原因，并且仍然是一个临床挑战，但并非所有侵袭性肿瘤。是转移性的，因此定义转移能力的决定因素并识别癌症患者可能发生转移或有残留疾病对于疾病的临床管理至关重要。异质性、无法从侵入前沿精确分离肿瘤细胞以及临床随访的机会有限数据对确定转移能力决定因素提出了重大挑战。在大约 15% 的 ccRCC 患者中观察到侵袭性血管内生长为肿瘤血栓。可以使用横截面成像（包括计算机化成像）准确识别侵袭性肿瘤扩展断层扫描和磁共振成像扫描对于切除的肿瘤分期很有价值。具有明确延伸至脉管系统的侵袭性原发性肿瘤，以识别 ccRCC 侵袭和约 50% 的 ccRCC 患者存在血管内肿瘤扩展。肾切除和治疗后发生转移，综合生存结果较差。具有血管内延伸的转移性和非转移性侵袭性 ccRCC 肿瘤的转录组学分析确定了转移能力的决定因素。我们的中心假设是侵袭性 ccRCC 肿瘤的转移能力取决于 PRRX1 驱动血管生成拟态和趋化细胞因子招募 CXCR2 阳性浸润免疫细胞的能力到促进远端器官传播和定植的侵入性前沿。在实验模型系统中对 PRRX1 和 CXCL1 配体进行基因操作导致了减弱转移。我们将研究 PRRX1 介导的血管生成拟态在驱动转移中的作用并评估我们还将阐明 CXCL1 在驱动中的作用。转移并评估 CXCR2 拮抗剂对转移进展的影响。将破译决定侵袭性 ccRCC 转移能力的病理生理机制并开发破坏转移能力的创新疗法，与当前的护理标准相结合治疗方案将有效控制转移性疾病。