干旱区生态环境知识资源中心(Arid): Bcl-xL Enforces a Slow-Cycling State Necessary for Survival in the Nutrient-Deprived Microenvironment of Pancreatic Cancer

Arid

DOI	10.1158/0008-5472.CAN-22-0431
	Bcl-xL Enforces a Slow-Cycling State Necessary for Survival in the Nutrient-Deprived Microenvironment of Pancreatic Cancer
	Sela, Yogev; Li, Jinyang; Maheswaran, Shivahamy; Norgard, Robert; Yuan, Salina; Hubbi, Maimon; Doepner, Miriam; Xu, Jimmy P.; Ho, Elaine S.; Mesaros, Clementina; Sheehan, Colin; Croley, Grace; Muir, Alexander; Blair, Ian A.; Shalem, Ophir; Dang, Chi V.; Stanger, Ben Z.
通讯作者	Stanger, B
来源期刊	CANCER RESEARCH
ISSN	0008-5472
EISSN	1538-7445
出版年	2022
卷号	82 期号:10 页码:1890-1908
英文摘要	Solid tumors possess heterogeneous metabolic microenvironments where oxygen and nutrient availability are plentiful (fertile regions) or scarce (arid regions). While cancer cells residing in fertile regions proliferate rapidly, most cancer cells in vivo reside in arid regions and exhibit a slow-cycling state that renders them chemoresistant. Here, we developed an in vitro system enabling systematic comparison between these populations via transcriptome analysis, metabolomic profiling, and whole-genome CRISPR screening. Metabolic deprivation led to pronounced transcriptional and metabolic reprogramming, resulting in decreased anabolic activities and distinct vulnerabilities. Reductions in anabolic, energy-consuming activities, particularly cell proliferation, were not simply byproducts of the metabolic challenge, but rather essential adaptations. Mechanistically, Bcl-xL played a central role in the adaptation to nutrient and oxygen deprivation. In this setting, Bcl-xL protected quiescent cells from the lethal effects of cell-cycle entry in the absence of adequate nutrients. Moreover, inhibition of Bcl-xL combined with traditional chemotherapy had a synergistic antitumor effect that targeted cycling cells. Bcl-xL expression was strongly associated with poor patient survival despite being confined to the slow-cycling fraction of human pancreatic cancer cells. These findings provide a rationale for combining traditional cancer therapies that target rapidly cycling cells with those that target quiescent, chemoresistant cells associated with nutrient and oxygen deprivation.
类型	Article
语种	英语
开放获取类型	Green Submitted, Bronze, Green Accepted
收录类别	SCI-E
WOS记录号	WOS:000799613300001
WOS关键词	TUMOR-CELLS ; PROTEINS ; POTENT ; MITOCHONDRIAL ; PROLIFERATION ; METABOLISM ; DISCOVERY ; APOPTOSIS ; OXYGEN ; KI-67
WOS类目	Oncology
WOS研究方向	Oncology
资源类型	期刊论文
条目标识符	http://119.78.100.177/qdio/handle/2XILL650/392052
推荐引用方式 GB/T 7714	Sela, Yogev,Li, Jinyang,Maheswaran, Shivahamy,et al. Bcl-xL Enforces a Slow-Cycling State Necessary for Survival in the Nutrient-Deprived Microenvironment of Pancreatic Cancer[J],2022,82(10):1890-1908.
APA	Sela, Yogev.,Li, Jinyang.,Maheswaran, Shivahamy.,Norgard, Robert.,Yuan, Salina.,...&Stanger, Ben Z..(2022).Bcl-xL Enforces a Slow-Cycling State Necessary for Survival in the Nutrient-Deprived Microenvironment of Pancreatic Cancer.CANCER RESEARCH,82(10),1890-1908.
MLA	Sela, Yogev,et al."Bcl-xL Enforces a Slow-Cycling State Necessary for Survival in the Nutrient-Deprived Microenvironment of Pancreatic Cancer".CANCER RESEARCH 82.10(2022):1890-1908.