Precision Medicine of Cancer

癌症精准医学

• 批准号: 10486867
• 负责人: Curtis Harris
• 金额: $ 254.5万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10486867
• 关键词: Acids; Adenocarcinoma Cell; African; Annual Reports; Anus; Bacteria; Bacterial Infections; Bioinformatics; Biological Assay; Biological Factors; Biological Markers; CA-19-9 Antigen; CD8B1 gene; COVID-19 pandemic; Cancer Patient; Cells; Cholestanes; Clinical; Collaborations; Contracts; Creatine; DNA Methylation; Data; Development; Diagnosis; Diagnostic; Disease; Environmental Exposure; Escherichia coli; Evaluation; Exposure to; Fluorescence-Activated Cell Sorting; Foundations; Frequencies; Genets; Glucuronides; Human; Human Resources; Hydrocortisone; Immune; Immunotherapy; Infection; Infiltration; Inflammatory; Inflammatory Response; Intrahepatic Cholangiocarcinoma; Investigation; Ions; KPC model; Laboratories; Lesion; Leukocytes; Lung; Lung Adenocarcinoma; Lung Neoplasms; Malignant Neoplasms; Malignant neoplasm of lung; Mass Spectrum Analysis; Measures; Mediating; Medical; Messenger RNA; MicroRNAs; Molecular; Molecular Analysis; Mus; Mutation; N-Acetylneuraminic Acid; Natural Immunity; Neutrophil Infiltration; Neutrophilic Infiltrate; PTPRC gene; Pathway interactions; Phenotype; Plasma; Play; Population; Prognosis; Property; Proteome; Recurrence; Reporting; Research; Resources; Role; Serum; Signal Transduction; Smoking; Squamous cell carcinoma; Statistical Data Interpretation; Sterility; Sulfate; T-Lymphocyte; TP53 gene; Taxonomy; Therapeutic; Time; Tissue-Specific Gene Expression; Tissues; Tumor Burden; Urine; adaptive immunity; base; bench to bedside; cancer biomarkers; cancer cell; cancer diagnosis; cancer initiation; cancer risk; cancer therapy; cancer type; cohort; cytokine; genome wide association study; health disparity; high risk; improved; individual patient; liquid biopsy; lung carcinogenesis; lung microbiome; lung tumorigenesis; metabolome; microbiome; microbiota; mouse model; neutrophil; novel; pathogenic Escherichia coli; patient subsets; personalized diagnostics; precision medicine; precision oncology; prognostic; programmed cell death ligand 1; programs; response; riboside; screening; therapeutic target; therapy outcome; transcriptome sequencing; tumor; tumor microenvironment; tumor progression; tumor-immune system interactions; tumorigenic; urinary; γδ T cells

Precision medicine in cancer is multifaceted and our research, following the bench to bedside approach, has led to significant discoveries that will advance the diagnostic and prognostic utilization of biomarkers and elucidate the role and mechanism the microbiome plays in lung carcinogenesis. In addition, researching health disparity remains a focus (Graff, M. et al., Am J Hum Genet. 108: 564-582, 2021; Jiang M. et al. Lung Cancer 152: 58-65, 2021) that build on the laboratory's legacy of having been the first to conduct GWAS in the US population of African heritage (Zanetti KA. et al., Lung Cancer 98: 33-42, 2016). Cancer Microbiome: A recent study of microbiota composition revealed an abundance of bacteria in several cancer types once thought to be sterile (Greathouse KL. et al., Cancer Cell 38: 158-160, 2020). We have discovered Acidovorax spp associated with TP53 mutations and smoking in both adenocarcinoma and squamous cell carcinoma. Using a mouse model of lung cancer, we show Acidovorax spp is a contributor, not a passenger, of lung carcinogenesis, via activation of proinflammatory lung neutrophils. Our data showed that mice exposed to A. temperans (Acidovorax temperans) had significantly larger tumor burden and more abundant lung lesions compared to PBS-instilled (sham) control mice. A. temperans instillation is deleterious to survival and repeated exposure accelerates lung tumor development in tumor-bearing mice, thus, A. temperans has a functional role in lung cancer development. Whole tissue RNA sequencing (RNAseq) comparing differential gene expression in A. temperans-instilled mice and sham controls showed a strong inflammatory response to A. temperans through MyD88-dependent signaling, a pathway essential to launch innate and adaptive immunity, and contributes to cancer progression. In collaboration with Romina Goldszmid, we investigated the changes in the tumor immune microenvironment upon instillations with A. temperans. Our fluorescence activated cell sorting (FACS) analysis results showed an increase of CD45+ve immune populations in the lungs of A. temperans-instilled mice driven by neutrophils, CD4+ve, CD8+ve, double negative (DN) T-cells as well as an increase in gamma-delta T cells. Overall, our results indicate that A. temperans increases infiltration of proinflammatory cells, which sustained over time, promote lung adenocarcinoma development. Neutrophil recruitment is exacerbated in the lungs of KPC mice upon challenge with A. temperans. The phenotype of the infiltrated neutrophils in A. temperans -instilled mice have increased frequency of CD44lowICAM1highSiglecF+PDL1+ neutrophils, previously characterized as long-lived, mature pro-tumorigenic tumor-associated neutrophils, important for lung tumor progression in KPC mice. RNAseq showed higher signature scores for activated and mature neutrophils in A. temperans-challenged mice. Bacterial exposure is likely the reason for neutrophil maturation, so we compared scores for a previously reported neutrophil signature of pathogenic Escherichia coli (E. coli) infection and found that A. temperans-instilled mice had higher signature scores for neutrophil maturation due to bacterial infection. Neutrophils are the dominant immune cell population in the tumor microenvironment of lung cancer patients and evidence shows that an increased ratio of circulating neutrophils to leukocytes is associated with poor prognosis, and worse response to therapy, including immunotherapy. Next is to develop a therapeutic mouse model and to validate the role of neutrophils in mediating A. temperans-induced lung tumorigenesis. Cancer Metabolome: Correlation of identified metabolites with specific cancers created biomarker profiles that can be utilized for non-invasion diagnostic and prognostic evaluation of many types of human cancer. Liquid biopsy of urine, serum and plasma are used to measure four biomarkers (creatine riboside (CR), N-acetylneuminic acid (NANA), cortisol sulfate (CS), and 27alpha-nor-5beta-cholestane-3aplpha, 7alpha, 12alpha 24alpha, 25alpha Pentol glucuronide (NCPG) of lung cancer by mass spectrometry (Haznadar, M. et al., Cancer Epidemiol. Biomarker Prev. 25:978-86, 2016). CR paired with other identified urinary metabolite biomarkers such as (NANA) improve diagnostic capability and reliability. These foundational studies validated the use of urinary metabolite screening leading to further investigation into biomarker association with human cancer. (Patel, DP. et al. J Pharm Biomed Anal. 191: 113596, 2020) And as mentioned in the 2020 annual report, urinary metabolite biomarker profiling could offer diagnostic and prognostic evaluation of intrahepatic cholangiocarcinoma (ICC). Employing UPLC-MS/MS, four metabolites, for the quantitation of metabolites CR, N-acetylneuraminic acid (NANA), cortisol sulfate, and a glucuronide fragmented ion designated as 561+, are significantly increased in HCC and ICC and are robust at classifying ICC in combination with a clinically utilized marker CA19-9. NCI-MD cohort were studied and observations verified by the TIGER-LC cohort. We determined properties that are significant for a biomarker to its use in CLIA based assays of biomarkers in liquid biopsy.

癌症中的精密医学是多方面的，我们的研究以卧床式方法为基础，导致了重大发现，这些发现将提高生物标志物的诊断和预后利用，并阐明微生物组在肺癌中的作用和机制。此外，研究健康差异仍然是一个重点（Graff，M。等，Am J HumGenet。108：564-582，2021; Jiang M.等人152：58-65，2021）是基于实验室的遗产，这些遗产是在非洲癌症中首次进行GWAS的gwas（ZaneTage 98），33 canny2 e。 2016）。癌症微生物组：最近对微生物群成分的研究表明，几种癌症类型的细菌曾经被认为是无菌的（Greathouse Kl.等，癌细胞38：158-160，2020）。我们发现了与TP53突变相关的酸伏烷spp，并在腺癌和鳞状细胞癌中吸烟。使用肺癌的小鼠模型，我们显示酸伏烷属SPP是通过激活促炎性肺嗜中性粒细胞的激活而不是肺癌发生的乘客。我们的数据表明，与PBS含有PBS含量（假）对照小鼠相比，暴露于A. temans（酸芳岛候选物）的小鼠具有明显更大的肿瘤负担和更丰富的肺部病变。 A.温质滴注对生存性是有害的，并且反复的暴露会加速肿瘤小鼠的肺部肿瘤的发展，因此，A。候选体在肺癌发育中具有功能作用。整个组织RNA测序（RNASEQ）比较了冠状动脉味的小鼠中的差异基因表达和假对照，通过MyD88依赖性信号传导对螺旋杆菌表现出强烈的炎症反应，这是发射先天和适应性免疫所必需的途径，并为癌症进展做出贡献。与Romina Goldszmid合作，我们调查了用A. temperans滴注肿瘤免疫微环境的变化。我们的荧光活化细胞分选（FACS）分析结果表明，由中性粒细胞，CD4+VE，CD8+VE，Double（DN）T细胞驱动的A. temper虫含量的小鼠的CD45+VE免疫种群增加，以及伽马 - 戴尔塔T细胞的增加。总体而言，我们的结果表明，随着时间的流逝，促炎细胞会增加促炎细胞的浸润，从而促进肺腺癌发育。伴有抗螺旋体的挑战时，在KPC小鼠的肺中，中性粒细胞的募集加剧。在烟曲霉灌注的小鼠中，浸润性嗜中性粒细胞的表型增加了CD44lowicam1highSigleCf+ pdl1+中性粒细胞的频率，以前被描述为长期寿命，成熟的pro肿瘤肿瘤肿瘤相关的中性粒细胞，对KPC小鼠的肺肿瘤进度。 RNASEQ显示出较高的a活化和成熟嗜中性粒细胞的特征分数。细菌暴露可能是嗜中性粒细胞成熟的原因，因此我们比较了先前报道的致病性大肠杆菌（大肠杆菌）感染的中性粒细胞特征的评分，发现A.含有温质的小鼠具有较高的因细菌感染引起的中性粒细胞成熟的特征评分。嗜中性粒细胞是肺癌患者肿瘤微环境中的主要免疫细胞群体，证据表明，循环中性粒细胞与白细胞的比率增加与预后不良有关，对治疗的反应较差，包括免疫疗法。接下来是开发一种治疗小鼠模型，并验证中性粒细胞在介导曲霉诱导的肺肿瘤发生中的作用。癌症代谢组：已鉴定的代谢产物与特定的癌症的相关性，可用于对许多类型的人类癌症的非染色诊断和预后评估，这些疾病可用于非侵袭性诊断和预后评估。 Liquid biopsy of urine, serum and plasma are used to measure four biomarkers (creatine riboside (CR), N-acetylneuminic acid (NANA), cortisol sulfate (CS), and 27alpha-nor-5beta-cholestane-3aplpha, 7alpha, 12alpha 24alpha, 25alpha Pentol glucuronide (NCPG) of通过质谱癌（Haznadar，M。Et Al。 HCC和ICC中硫酸皮质醇和葡萄糖醛酸碎片碎片离子显着增加，并且在将ICC与临床使用的标记CA19-9结合使用时非常强大。研究了NCI-MD队列，并通过Tiger-LC队列验证了观察结果。我们确定了对生物标志物在CLIA基于液体活检中的生物标志物中使用的特性。