Plastic States Associated with Cellular Stress and Malignancy: Insights for Prevention and Treatment of Lethal Metaplastic Cancers

与细胞应激和恶性肿瘤相关的塑性状态：预防和治疗致命化生性癌症的见解

• 批准号: 10318925
• 负责人: Thea D Tlsty
• 金额: $ 81.5万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-19 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10318925
• 关键词: Biological Markers; Biology; Carcinoma; Cells; Cellular Stress; Chronic; Classification; Esophageal Adenocarcinoma; Etiology; Goals; Incidence; Inflammation; Lesion; Malignant - descriptor; Malignant Neoplasms; Metaplasia; Metaplastic Carcinoma; Metaplastic carcinoma of the breast; Modernization; Molecular; Phenotype; Physicians; Precancerous Conditions; Prevention; Preventive; Prognosis; Role; Signal Pathway; Site; Stomach Carcinoma; Therapeutic; Tissues; cancer invasiveness; cancer prevention; cell type; clinical practice; insight; malignant stomach neoplasm; mortality; novel; premalignant; public health relevance; rational design; regenerative cell; response; stem; therapeutic target; tissue injury; triple-negative invasive breast carcinoma

 DESCRIPTION (provided by applicant): Our long-term goals are to find effective preventive and therapeutic approaches for a group of carcinomas that are disproportionately responsible for cancer mortality worldwide. This proposal will seek to identify the cell of origin for a group f aggressive malignancies from disparate sites that share a common etiology of a metaplastic response to chronic inflammation. Our previous studies, and the novel insights they have generated, provide us with a compelling hypothesis that defies the current dogma and classification of these selected malignancies. We propose that select subsets of carcinomas, exemplified in this proposal by esophageal adenocarcinoma, gastric carcinoma of the indeterminate type and metaplastic breast cancers, arise from unique phenotypically plastic cells that confer aggressive phenotypes with extremely poor prognosis. These subsets of carcinomas are typified by the presence of metaplastic tissue derivatives in the pre-malignant and malignant lesions. Metaplasia, a protective adaptive tissue response where one cell type is replaced by another cell type not typically present in that tissue, is indicative of chronic tissue injury and associated with increased incidence of cancer. Unraveling the biology of these "metaplastic carcinomas" will allow us to overcome barriers to the identification of predisposing conditions and the subsequent activation of the cells-of-origin leading to lethal metaplastic carcinomas and to develop biomarkers to identify those premalignant lesions that will progress to invasive cancer. Identification and targeting of signaling pathways that control progression of these cells would allow us to design rational therapeutics that target the invasive state of these carcinomas. Finally, we also propose a novel preventive approach to reduce formation of the pre-malignant state that underlies these malignancies. Realization of our goals would change clinical practice and allow physicians to halt these cancers before they form. We propose to: (1) determine the role of specific stem/regenerative cells in initiation and progression esophageal adenocarcinomas, gastric cancers of indeterminate type and a subset of triple negative breast cancers, i.e. metaplastic breast cancers. We will also (2) identify distinct molecular features (cellular states) and match them with an optimal approach for (3) targeted prevention and (4) therapy. The connection between chronic inflammation and malignancy is well known; however despite an understanding of the causal insults, the incidences of these malignancies are increasing in the modern world and significantly contribute to cancer mortality. If successful, the goals of this proposal would delineate a therapeutic paradigm that could reduce mortality from this subset of cancers and fundamentally alter our approach to cancer prevention.

 描述（由适用提供）：我们的长期目标是为一组对全球癌症死亡率不成比例的癌寻求有效的预防和治疗方法。该提案将寻求从不同部位的F攻击性恶性肿瘤中确定原始细胞，这些恶性肿瘤具有对慢性炎症反应的共同病因。我们以前的研究及其产生的新见解为我们提供了一个令人信服的假设，该假设定义了当前的教条和分类这些选定的恶性肿瘤。我们提出，在该提案中选择的癌亚群是由食管腺癌，不确定类型的胃癌和化生性乳腺癌的胃癌，是由独特的表词塑料细胞引起的，这些细胞赋予了独特的表型塑料细胞，这些细胞允许积极的表型具有极低的预后。这些癌的子集的特征是在恶性病变和恶性病变中存在化生组织衍生物。 Metaplasia是一种受保护的自适应组织反应，其中一种细胞类型被通常不存在该组织中不存在的另一种细胞类型代替，这表明慢性组织 损伤并与癌症发病率增加有关。阐明这些“化生癌的生物学”将使我们能够克服鉴定易感性疾病的障碍，并随后激活 - 产卵细胞导致致命的化生型癌，并开发生物标志物，以识别那些将会识别出那些前往侵入性癌症的较小者。控制这些细胞进展的信号通路的识别和靶向将使我们能够设计靶向这些癌的侵入性状态的理论理论。最后，我们还提出了一种新型的预防方法，以减少构成这些恶性肿瘤的恶性前状态的形成。实现我们的目标将改变临床实践，并允许医生在形成这些癌症之前停止这些癌症。我们建议：（1）确定特异性茎/再生细胞在起始和进展性食管腺癌，不确定类型的胃癌和三重阴性乳腺癌的子集中，即化学肿瘤乳腺癌的作用。我们还将（2）确定不同的分子特征（细胞状态），并使用（3）靶向预防和（4）治疗的最佳方法匹配它们。慢性感染与恶性肿瘤之间的联系是众所周知的。然而，尽管了解了因果感染，但这些恶性肿瘤的发明在现代世界中正在增加，并显着导致癌症死亡率。如果成功， 该提案的目标将描述一种治疗范式，该范式可以从此癌症的一部分中降低死亡率，并从根本上改变我们的预防癌症方法。

项目成果

Stromal directives can control cancer.

基质指令可以控制癌症。

• DOI: 10.1126/science.aaw2368
• 发表时间: 2019
• 期刊: Science (New York, N.Y.)
• 作者: Tlsty,TheaD;Gascard,Philippe
• 通讯作者: Gascard,Philippe

Carcinoma-associated fibroblasts: orchestrating the composition of malignancy.

• DOI: 10.1101/gad.279737.116
• 发表时间: 2016-05-01
• 期刊: Genes & development
• 影响因子: 10.5
• 作者: Gascard P;Tlsty TD
• 通讯作者: Tlsty TD

SOX2, OCT3/4 and NANOG expression and cellular plasticity in rare human somatic cells requires CD73.

稀有人类体细胞中 SOX2、OCT3/4 和 NANOG 的表达和细胞可塑性需要 CD73。

• DOI: 10.1016/j.cellsig.2016.09.008
• 发表时间: 2016
• 期刊: Cellular signalling
• 影响因子: 4.8
• 作者: Pan,Deng;Roy,Somdutta;Gascard,Philippe;Zhao,Jianxin;Chen-Tanyolac,Chira;Tlsty,TheaD
• 通讯作者: Tlsty,TheaD

Loss of PPARγ activity characterizes early protumorigenic stromal reprogramming and dictates the therapeutic window of opportunity.

• DOI: 10.1073/pnas.2303774120
• 发表时间: 2023-10-17
• 期刊: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• 影响因子: 11.1
• 作者: Caruso, Joseph A.;Wang, Xianhong;Murrow, Lyndsay M.;Rodriguez, Carlos Ivan;Chen-Tanyolac, Chira;Vu, Lisa;Chen, Yunn-Yi;Gascard, Philippe;Gartner, Zev J.;Kerlikowske, Karla;Tlsty, Thea D.
• 通讯作者: Tlsty, Thea D.