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.



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

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.

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