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Metabolic Reprogramming in Human Cancer Patients and Patient-Derived Models. 人类癌症患者和患者衍生模型的代谢重编程。
IF 7.8 2区 医学
Cold Spring Harbor perspectives in medicine Pub Date : 2024-07-15 DOI: 10.1101/cshperspect.a041552
Teresa W-M Fan, Richard M Higashi, Andrew N Lane
{"title":"Metabolic Reprogramming in Human Cancer Patients and Patient-Derived Models.","authors":"Teresa W-M Fan, Richard M Higashi, Andrew N Lane","doi":"10.1101/cshperspect.a041552","DOIUrl":"https://doi.org/10.1101/cshperspect.a041552","url":null,"abstract":"<p><p>Stable isotope-resolved metabolomics delineates reprogrammed intersecting metabolic networks in human cancers. Knowledge gained from in vivo patient studies provides the \"benchmark\" for cancer models to recapitulate. It is particularly difficult to model patients' tumor microenvironment (TME) with its complex cell-cell/cell-matrix interactions, which shapes metabolic reprogramming crucial to cancer development/drug resistance. Patient-derived organotypic tissue cultures (PD-OTCs) represent a unique model that retains an individual patient's TME. PD-OTCs of non-small-cell lung cancer better recapitulated the in vivo metabolic reprogramming of patient tumors than the patient-derived tumor xenograft (PDTX), while enabling interrogation of immunometabolic response to modulators and TME-dependent resistance development. Patient-derived organoids (PDOs) are also good models for reconstituting TME-dependent metabolic reprogramming and for evaluating therapeutic responses. Single-cell based 'omics on combinations of PD-OTC and PDO models will afford an unprecedented understanding on TME dependence of human cancer metabolic reprogramming, which should translate into the identification of novel metabolic targets for regulating TME interactions and drug resistance.</p>","PeriodicalId":10452,"journal":{"name":"Cold Spring Harbor perspectives in medicine","volume":" ","pages":""},"PeriodicalIF":7.8,"publicationDate":"2024-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141619556","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Targeting Hyperactive Ras Signaling in Pediatric Cancer. 靶向小儿癌症中亢进的 Ras 信号
IF 7.8 2区 医学
Cold Spring Harbor perspectives in medicine Pub Date : 2024-07-15 DOI: 10.1101/cshperspect.a041572
Anya Levinson, Kevin Shannon, Benjamin J Huang
{"title":"Targeting Hyperactive Ras Signaling in Pediatric Cancer.","authors":"Anya Levinson, Kevin Shannon, Benjamin J Huang","doi":"10.1101/cshperspect.a041572","DOIUrl":"10.1101/cshperspect.a041572","url":null,"abstract":"<p><p>Somatic <i>RAS</i> mutations are among the most frequent drivers in pediatric and adult cancers. Somatic <i>KRAS</i>, <i>NRAS</i>, and <i>HRAS</i> mutations exhibit distinct tissue-specific predilections. Germline <i>NF1</i> and <i>RAS</i> mutations in children with neurofibromatosis type 1 and other RASopathy developmental disorders have provided new insights into Ras biology. In many cases, these germline mutations are associated with increased cancer risk. Promising targeted therapeutic strategies for pediatric cancers and neoplasms with <i>NF1</i> or <i>RAS</i> mutations include inhibition of downstream Ras effector pathways, directly inhibiting the signal output of oncogenic Ras proteins and associated pathway members, and therapeutically targeting Ras posttranslational modifications and intracellular trafficking. Acquired drug resistance to targeted drugs remains a significant challenge but, increasingly, rational drug combination approaches have shown promise in overcoming resistance. Developing predictive preclinical models of childhood cancers for drug testing is a high priority for the field of pediatric oncology.</p>","PeriodicalId":10452,"journal":{"name":"Cold Spring Harbor perspectives in medicine","volume":" ","pages":""},"PeriodicalIF":7.8,"publicationDate":"2024-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141619558","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Principles in the Development of Contemporary Treatment of Childhood Malignancies: The First 75 Years. 当代儿童恶性肿瘤治疗发展的原则：前 75 年。
IF 7.8 2区 医学
Cold Spring Harbor perspectives in medicine Pub Date : 2024-07-15 DOI: 10.1101/cshperspect.a041634
Katie A Greenzang, Stephen E Sallan
{"title":"Principles in the Development of Contemporary Treatment of Childhood Malignancies: The First 75 Years.","authors":"Katie A Greenzang, Stephen E Sallan","doi":"10.1101/cshperspect.a041634","DOIUrl":"https://doi.org/10.1101/cshperspect.a041634","url":null,"abstract":"<p><p>Over the last 75 years, pediatric cancer has gone from nearly universally fatal, to having a >80% chance of long-term survival. Below we share highlights in this 75-year history, beginning with the \"birth\" of chemotherapy in treating childhood leukemia, through the development of multiagent chemotherapy, risk-stratified therapy, the use of molecular strategies in diagnosis and treatment, and adapting treatment to the needs of particularly vulnerable patient groups such as adolescents and young adults (AYAs). While pediatric leukemia treatment demonstrates the ever-improving cures achieved through iterative incorporation of novel discoveries, this experience is contrasted with that of osteosarcoma, where scientific advances made over recent decades have yet to be translated into meaningful improvements in long-term survival. We conclude with a brief overview of current areas of focus, including precision medicine, immunotherapy, and other treatment advancements, yet describe the need to couple these scientific breakthroughs with consideration of equitable access and evaluation of the long-term impacts of these \"newer\" therapies in survivorship. Substantial further work is needed to achieve our goal of curing all children with cancer as harmlessly as possible.</p>","PeriodicalId":10452,"journal":{"name":"Cold Spring Harbor perspectives in medicine","volume":" ","pages":""},"PeriodicalIF":7.8,"publicationDate":"2024-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141619557","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Imaging Tumor Metabolism. 肿瘤代谢成像。
IF 7.8 2区 医学
Cold Spring Harbor perspectives in medicine Pub Date : 2024-07-15 DOI: 10.1101/cshperspect.a041551
Thomas Ruan, Kayvan R Keshari
{"title":"Imaging Tumor Metabolism.","authors":"Thomas Ruan, Kayvan R Keshari","doi":"10.1101/cshperspect.a041551","DOIUrl":"https://doi.org/10.1101/cshperspect.a041551","url":null,"abstract":"<p><p>Molecular imaging-the mapping of molecular and cellular processes in vivo-has the unique capability to interrogate cancer metabolism in its spatial contexts. This work describes the usage of the two most developed modalities for imaging metabolism in vivo: positron emission tomography (PET) and magnetic resonance (MR). These techniques can be used to probe glycolysis, glutamine metabolism, anabolic metabolism, redox state, hypoxia, and extracellular acidification. This review aims to provide an overview of the strengths and limitations of currently available molecular imaging strategies.</p>","PeriodicalId":10452,"journal":{"name":"Cold Spring Harbor perspectives in medicine","volume":" ","pages":""},"PeriodicalIF":7.8,"publicationDate":"2024-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141619554","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Patient-Derived-Xenografts in Mice: A Preclinical Platform for Cancer Research. 小鼠中的患者衍生的X基因移植物：癌症研究的临床前平台。
IF 7.8 2区 医学
Cold Spring Harbor perspectives in medicine Pub Date : 2024-07-01 DOI: 10.1101/cshperspect.a041381
Emiliano Cocco, Elisa de Stanchina
{"title":"Patient-Derived-Xenografts in Mice: A Preclinical Platform for Cancer Research.","authors":"Emiliano Cocco, Elisa de Stanchina","doi":"10.1101/cshperspect.a041381","DOIUrl":"10.1101/cshperspect.a041381","url":null,"abstract":"<p><p>The use of patient-derived xenografts (PDXs) has dramatically improved drug development programs. PDXs (1) reproduce the pathological features and the genomic profile of the parental tumors more precisely than other preclinical models, and (2) more faithfully predict therapy response. However, PDXs have limitations. These include the inability to completely capture tumor heterogeneity and the role of the immune system, the low engraftment efficiency of certain tumor types, and the consequences of the human-host interactions. Recently, the use of novel mouse strains and specialized engraftment techniques has enabled the generation of \"humanized\" PDXs, partially overcoming such limitations. Importantly, establishing, characterizing, and maintaining PDXs is costly and requires a significant regulatory, administrative, clinical, and laboratory infrastructure. In this review, we will retrace the historical milestones that led to the implementation of PDXs for cancer research, review the most recent innovations in the field, and discuss future avenues to tackle deficiencies that still exist.</p>","PeriodicalId":10452,"journal":{"name":"Cold Spring Harbor perspectives in medicine","volume":" ","pages":""},"PeriodicalIF":7.8,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11216185/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10213390","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Current Status of Clinical Trials Design and Outcomes in Retinal Gene Therapy. 视网膜基因治疗的临床试验设计和结果现状。
IF 7.8 2区 医学
Cold Spring Harbor perspectives in medicine Pub Date : 2024-07-01 DOI: 10.1101/cshperspect.a041301
Boris Rosin, Eyal Banin, Jose-Alain Sahel
{"title":"Current Status of Clinical Trials Design and Outcomes in Retinal Gene Therapy.","authors":"Boris Rosin, Eyal Banin, Jose-Alain Sahel","doi":"10.1101/cshperspect.a041301","DOIUrl":"10.1101/cshperspect.a041301","url":null,"abstract":"<p><p>With the rapid expansion of methods encompassed by the term gene therapy, new trials exploring the safety and efficacy of these methods are initiated more frequently. As a result, important questions arise pertaining the design of these trials and patient participation. One of the most important aspects of any clinical trial is the ability to measure the trial's outcome in a manner that will reflect the effect of the treatment and allow its quantification, whether the trial is aimed at preservation or restoration of retinal cells (photoreceptors and others), vision, or both. Here we will review the existing methods for quantification of trial outcomes, stressing the importance of assessing the participant's visual function and not just visual acuity. We will also describe the key considerations in trial design. Finally, as patient safety remains the primary concern in any trial participation, we will outline the key principles in that regard.</p>","PeriodicalId":10452,"journal":{"name":"Cold Spring Harbor perspectives in medicine","volume":" ","pages":""},"PeriodicalIF":7.8,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11216172/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10215521","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
The Chicken or the Egg Dilemma: Understanding the Interplay between the Immune System and the β Cell in Type 1 Diabetes. 鸡还是蛋的两难选择：了解 1 型糖尿病中免疫系统与 β 细胞之间的相互作用。
IF 7.8 2区 医学
Cold Spring Harbor perspectives in medicine Pub Date : 2024-07-01 DOI: 10.1101/cshperspect.a041591
Maria Skjøtt Hansen, Pravil Pokharel, Jon Piganelli, Lori Sussel
{"title":"The Chicken or the Egg Dilemma: Understanding the Interplay between the Immune System and the β Cell in Type 1 Diabetes.","authors":"Maria Skjøtt Hansen, Pravil Pokharel, Jon Piganelli, Lori Sussel","doi":"10.1101/cshperspect.a041591","DOIUrl":"10.1101/cshperspect.a041591","url":null,"abstract":"<p><p>In this review, we explore the complex interplay between the immune system and pancreatic β cells in the context of type 1 diabetes (T1D). While T1D is predominantly considered a T-cell-mediated autoimmune disease, the inability of human leukocyte antigen (HLA)-risk alleles alone to explain disease development suggests a role for β cells in initiating and/or propagating disease. This review delves into the vulnerability of β cells, emphasizing their susceptibility to endoplasmic reticulum (ER) stress and protein modifications, which may give rise to neoantigens. Additionally, we discuss the role of viral infections as contributors to T1D onset, and of genetic factors with dual impacts on the immune system and β cells. A greater understanding of the interplay between environmental triggers, autoimmunity, and the β cell will not only lead to insight as to why the islet β cells are specifically targeted by the immune system in T1D but may also reveal potential novel therapeutic interventions.</p>","PeriodicalId":10452,"journal":{"name":"Cold Spring Harbor perspectives in medicine","volume":" ","pages":""},"PeriodicalIF":7.8,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141476107","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Mouse Models to Evaluate the Functional Role of the Tumor Microenvironment in Cancer Progression and Therapy Responses. 评估肿瘤微环境在癌症进展和治疗反应中的功能作用的小鼠模型
IF 7.8 2区 医学
Cold Spring Harbor perspectives in medicine Pub Date : 2024-07-01 DOI: 10.1101/cshperspect.a041411
Kathleen M McAndrews, Krishnan K Mahadevan, Raghu Kalluri
{"title":"Mouse Models to Evaluate the Functional Role of the Tumor Microenvironment in Cancer Progression and Therapy Responses.","authors":"Kathleen M McAndrews, Krishnan K Mahadevan, Raghu Kalluri","doi":"10.1101/cshperspect.a041411","DOIUrl":"10.1101/cshperspect.a041411","url":null,"abstract":"<p><p>The tumor microenvironment (TME) is a complex ecosystem of both cellular and noncellular components that functions to impact the evolution of cancer. Various aspects of the TME have been targeted for the control of cancer; however, TME composition is dynamic, with the overall abundance of immune cells, endothelial cells (ECs), fibroblasts, and extracellular matrix (ECM) as well as subsets of TME components changing at different stages of progression and in response to therapy. To effectively treat cancer, an understanding of the functional role of the TME is needed. Genetically engineered mouse models have enabled comprehensive insight into the complex interactions within the TME ecosystem that regulate disease progression. Here, we review recent advances in mouse models that have been employed to understand how the TME regulates cancer initiation, progression, metastasis, and response to therapy.</p>","PeriodicalId":10452,"journal":{"name":"Cold Spring Harbor perspectives in medicine","volume":" ","pages":""},"PeriodicalIF":7.8,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11216184/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139402161","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Role of Tumor Cell Intrinsic and Host Autophagy in Cancer. 肿瘤细胞内在自噬和宿主自噬在癌症中的作用
IF 7.8 2区 医学
Cold Spring Harbor perspectives in medicine Pub Date : 2024-07-01 DOI: 10.1101/cshperspect.a041539
Jessie Yanxiang Guo, Eileen White
{"title":"Role of Tumor Cell Intrinsic and Host Autophagy in Cancer.","authors":"Jessie Yanxiang Guo, Eileen White","doi":"10.1101/cshperspect.a041539","DOIUrl":"10.1101/cshperspect.a041539","url":null,"abstract":"<p><p>Macroautophagy (autophagy hereafter) is an intracellular nutrient scavenging pathway induced by starvation and other stressors whereby cellular components such as organelles are captured in double-membrane vesicles (autophagosomes), whereupon their contents are degraded through fusion with lysosomes. Two main purposes of autophagy are to recycle the intracellular breakdown products to sustain metabolism and survival during starvation and to eliminate damaged or excess cellular components to suppress inflammation and maintain homeostasis. In contrast to most normal cells and tissues in the fed state, tumor cells up-regulate autophagy to promote their growth, survival, and malignancy. This tumor-cell-autonomous autophagy supports elevated metabolic demand and suppresses tumoricidal activation of the innate and adaptive immune responses. Tumor-cell-nonautonomous (e.g., host) autophagy also supports tumor growth by maintaining essential tumor nutrients in the circulation and tumor microenvironment and by suppressing an antitumor immune response. In the setting of cancer therapy, autophagy is a resistance mechanism to chemotherapy, targeted therapy, and immunotherapy. Thus, tumor and host autophagy are protumorigenic and autophagy inhibition is being examined as a novel therapeutic approach to treat cancer.</p>","PeriodicalId":10452,"journal":{"name":"Cold Spring Harbor perspectives in medicine","volume":" ","pages":""},"PeriodicalIF":7.8,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11216174/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139520131","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Integrating Omics into Functional Biomarkers of Type 1 Diabetes. 将 Omics 整合到 1 型糖尿病的功能生物标记中。
IF 7.8 2区 医学
Cold Spring Harbor perspectives in medicine Pub Date : 2024-07-01 DOI: 10.1101/cshperspect.a041602
S Alice Long, Peter S Linsley
{"title":"Integrating Omics into Functional Biomarkers of Type 1 Diabetes.","authors":"S Alice Long, Peter S Linsley","doi":"10.1101/cshperspect.a041602","DOIUrl":"10.1101/cshperspect.a041602","url":null,"abstract":"<p><p>Biomarkers are critical to the staging and diagnosis of type 1 diabetes (T1D). Functional biomarkers offer insights into T1D immunopathogenesis and are often revealed using \"omics\" approaches that integrate multiple measures to identify involved pathways and functions. Application of the omics biomarker discovery may enable personalized medicine approaches to circumvent the more recently appreciated heterogeneity of T1D progression and treatment. Use of omics to define functional biomarkers is still in its early years, yet findings to date emphasize the role of cytokine signaling and adaptive immunity in biomarkers of progression and response to therapy. Here, we share examples of the use of omics to define functional biomarkers focusing on two signatures, T-cell exhaustion and T-cell help, which have been associated with outcomes in both the natural history and treatment contexts.</p>","PeriodicalId":10452,"journal":{"name":"Cold Spring Harbor perspectives in medicine","volume":" ","pages":""},"PeriodicalIF":7.8,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11216170/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141075805","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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