Steady states and cellular transitions associated with carcinogenesis and tumorprogression

与癌发生和肿瘤进展相关的稳态和细胞转变

• 批准号: 10249961
• 负责人: James R. Heath
• 金额: $ 67.07万
• 依托单位: INSTITUTE FOR SYSTEMS BIOLOGY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-08 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10249961
• 关键词: BRAF gene; Biological; Biological Assay; Breast; Cancer Model; Cancerous; Cell Cycle Kinetics; Cell Line; Cell model; Cells; Cellular Assay; Chemicals; Combined Modality Therapy; Complement; Coupled; Data; Dose; Drug Tolerance; Drug resistance; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Exposure to; FRAP1 gene; Freedom; Genes; Genotype; Glioblastoma; Goals; Growth; Human; Immunotherapy; Ising model; Joints; Kinetics; Knowledge; Laws; Maintenance; Malignant Neoplasms; Malignant neoplasm of brain; Measurement; Measures; Melanoma Cell; Metabolic; Metabolism; Metastatic Melanoma; Modeling; Modification; Nature; Neural Crest; Outcome; Output; Patients; Pharmaceutical Preparations; Phase Transition; Phenotype; Phosphoproteins; Physics; Process; Proteins; Proteomics; Regimen; Research; Resistance; Resistance development; Science; Signal Transduction; Site; System; Temperature; Testing; Theoretical Studies; Theoretical model; Work; base; cancer cell; cancer drug resistance; carcinogenesis; chemical carcinogen; cigarette smoke; cytokine; design; drug development; exome sequencing; experimental study; genetic regulatory protein; improved; in silico; in vivo evaluation; inhibitor/antagonist; melanocyte; melanoma; mutant; physical model; programs; protein metabolite; response; targeted treatment; theories; therapy design; transcriptome sequencing; tumor; tumor growth; tumor progression

Project Summary/Abstract Cellular transitions are fundamental to many steps of carcinogenesis and tumor progression. Such transitions are broadly studied, but general models have been historically limited to qualitative descriptions. This contrasts with phase transitions in physical systems, which are well characterized within the context of the physico- chemical laws, and can be partially understood, in a predictive capacity, using simple, precise models such as the Ising model. Such models are based upon a system of interacting lattice sites. A parameter (e.g. Temperature) is varied, and the fluctuations of the lattice sites are analyzed as the system approaches and passes through a critical point. All critical system-specific details are captured in the interactions between the lattice sites, and the models can yield specific, experimentally verifiable predictions. Ising-like in silico models have guided theoretical studies of transitions in various gene or protein regulatory networks, although resultant predictions can be challenging to experimentally test. We seek a general approach where the experimental input is a statistically large number of single cell measurements, with many protein and metabolite analytes quantitatively measured per cell. From this data we capture the fluctuations and thereby determine the analyte-analyte correlations. In an Ising model analogy, such measurements define the site interactions. These inputs permit straightforward theoretic models for resolving cellular steady states, transitions between steady states, and for making testable predictions. Studies of the chemically-induced-carcinogenesis transition provide preliminary data/proof of concept. For Aim 1 we develop a picture of cancer cell steady states using integrated metabolic and proteomic single cell assays on cancer models of Glioblastoma Multiforme and Melanoma. In Aims 2 and 3 we expand this approach to two apparent cellular transitions associated with resistance against targeted therapies: the adaptation of heterogeneous brain cancers to certain targeted inhibitors, and a drug-induced cellular de-differentiation observed in melanomas and other tumors in response to immunotherapy and targeted inhibitors. All aims are joint experiment/theory aims. Aims 2-3 involve in vivo testing of predictions, as well as exome sequencing and global RNA-seq kinetic studies to complement the single cell kinetic analyses. Anticipated outcomes of the work include a general, quantitative approach towards describing cellular transitions associated with cancer. Further, we propose to mine those descriptions of cellular transitions to identify therapy combinations that are designed to hit targets that drive tumor growth, as well as those that drive the transition (and thus promote resistance) Preliminary data to support of this goal is provided. Additionally, guidance for non-continuous therapy dosing (e.g. metronomic or pulsatile regimens) that exploit knowledge of the kinetics, barriers, and reversibility of the transition to resistance is anticipated

项目总结/文摘

项目成果

Raman-guided subcellular pharmaco-metabolomics for metastatic melanoma cells.

• DOI: 10.1038/s41467-020-18376-x
• 发表时间: 2020-09-24
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Du J;Su Y;Qian C;Yuan D;Miao K;Lee D;Ng AHC;Wijker RS;Ribas A;Levine RD;Heath JR;Wei L
• 通讯作者: Wei L

Resolution of tissue signatures of therapy response in patients with recurrent GBM treated with neoadjuvant anti-PD1.

• DOI: 10.1038/s41467-021-24293-4
• 发表时间: 2021-06-29
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Lu Y;Ng AHC;Chow FE;Everson RG;Helmink BA;Tetzlaff MT;Thakur R;Wargo JA;Cloughesy TF;Prins RM;Heath JR
• 通讯作者: Heath JR

Surface Immobilization of Redox-Labile Fluorescent Probes: Enabling Single-Cell Co-Profiling of Aerobic Glycolysis and Oncogenic Protein Signaling Activities.

• DOI: 10.1002/anie.201803034
• 发表时间: 2018-09-03
• 期刊: Angewandte Chemie (International ed. in English)
• 作者: Li Z;Cheng H;Shao S;Lu X;Mo L;Tsang J;Zeng P;Guo Z;Wang S;Nathanson DA;Heath JR;Wei W;Xue M
• 通讯作者: Xue M

Single-cell profiling of D-2-hydroxyglutarate using surface-immobilized resazurin analogs.

• DOI: 10.1016/j.bios.2021.113368
• 发表时间: 2021-10-15
• 期刊: Biosensors & bioelectronics
• 影响因子: 12.6
• 作者: Cheng H;Li Z;Guo Z;Shao S;Mo L;Wei W;Xue M
• 通讯作者: Xue M

4D electron microscopy of T cell activation.

T 细胞激活的 4D 电子显微镜。

• DOI: 10.1073/pnas.1914078116
• 发表时间: 2019
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1
• 作者: Lu,Yue;Yoo,Byung-Kuk;Ng,AlphonsusHC;Kim,Jungwoo;Yeom,Sinchul;Tang,Jau;Lin,MiloM;Zewail,AhmedH;Heath,JamesR
• 通讯作者: Heath,JamesR