ccRCC Metastatic Competency Determinants

ccRCC 转移能力决定因素

• 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
• 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

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，即癌细胞通过血管系统从浸润性原发肿瘤向远端器官扩散 或者淋巴管是大多数患者死亡的原因，仍然是临床上的一个挑战。不是所有的侵袭性肿瘤 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 有可能发生转移或有残留病变是临床治疗疾病的关键。瘤内 异质性，无法准确地将肿瘤细胞从侵袭前沿分离出来，以及临床随访的机会有限- UP数据对识别转移性能力决定因素提出了重大挑战。 大约15%的肾细胞癌患者有侵袭性血管内生长，表现为癌栓。这 使用包括计算机化的横断面成像可以准确地识别侵袭性肿瘤的扩展 断层扫描和磁共振成像扫描对肿瘤分期很有价值。我们调查了切除的 侵袭性原发肿瘤清楚地延伸到血管系统以确定ccRCC的侵袭和 转移决定因素。大约50%的慢性肾细胞癌患者有血管内肿瘤扩展 肾切除和治疗后发生转移，预后较差。全面 转移性和非转移性侵袭性肾细胞癌血管内延伸的转录学分析 确定转移能力决定因素。 我们的中心假设是侵袭性肾细胞癌的转移能力依赖于Prrx1驱动 血管生成拟态与趋化细胞因子募集CXCR2阳性浸润性免疫细胞的能力 到侵袭性前线，促进传播和定植到远端器官。药理学和条件性 在实验模型系统中Prrx1和CXCL1配体的遗传操作导致衰减 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 转化生长因子-β抑制剂对肿瘤转移的影响。我们还将阐明CXCL1在驾驶中的作用 并评估CXCR2拮抗剂对转移进展的影响。我们期待着这个项目 能否破译决定侵袭性肾细胞癌转移能力的病理生理机制 破坏转移能力的创新疗法，与目前的护理标准相结合 这些方案将导致对转移性疾病的有效管理。