Tipping cancer cells over the edge: the context-dependent cost of high ploidy

AbstractInhibition of programmed cell death pathways is frequently observed in cancer cells where it functions to facilitate tumor progression. However, some proteins involved in the regulation of cell death function dichotomously to both promote and inhibit cell death depending on the cellular context. As such, understanding how cell death proteins are regulated in a context-dependent fashion in cancer cells is of utmost importance. We have uncovered evidence that cellular FLICE-like Inhibitory Protein (c-FLIP), a well-known anti-apoptotic protein, is often downregulated in tumor tissue when compared to adjacent normal tissue. These data argue that c-FLIP may have activity distinct from its canonical role in antagonizing cell death. Interestingly, we have discovered that detachment from extracellular matrix (ECM) serves as a signal to elevate c-FLIP transcription and that oncogenic signaling blocks ECM-detachment-induced c-FLIP elevation. In addition, our data reveal that downregulation of c-FLIP promotes luminal filling in mammary acini and that c-FLIP overexpression in cancer cells inhibits colony formation in cells exposed to ECM-detachment. Taken together, our study reveals an unexpected, non-apoptotic role for c-FLIP during ECM-detachment and raises the possibility that c-FLIP may have context-dependent roles during tumorigenesis.

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Instructed-Assembly as Context-Dependent Nanoscale Signals for Death and Morphogenesis of Cells

10.26434/chemrxiv.7581590 ◽

2019 ◽

Author(s):

Huaimin Wang ◽

Zhaoqianqi Feng ◽

Bing Xu

Keyword(s):

Cell Death ◽

Enzyme Activity ◽

Tumor Microenvironment ◽

Cancer Cells ◽

Drug Screening ◽

Cell Behavior ◽

Biological Functions ◽

Cell Spheroids ◽

Cellular Environment ◽

Context Dependent

Context-dependent signaling, as a ubiquitous phenomenon in nature, is a dynamic molecular process at nano- and microscales, but how to mimic its essence using non-covalent synthesis in cellular environment has yet to be developed. Here we show a dynamic continuum of non-covalent filaments formed by instructed-assembly (iA) of a supramolecular phosphoglycopeptide (sPGP) as context-dependent signals for controlling death and morphogenesis of cells. Specifically, while enzymes (i.e., ectophosphatases) on cancer cells catalyze the formation of the filaments of the sPGP to result in cell death, damping the enzyme activity induces 3D cell spheroids. Similarly, relying on the ratio of stromal and cancer cells in a co-culture to modulate the expression of the ectophosphatase, the iA process enables cell spheroids. The spheroids act as a mimic of tumor microenvironment for drug screening. As the first demonstration of iA as multifunctional processes according to local enzyme activity for controlling cell behavior, this work illustrates context-dependent biological functions of non-covalent synthesis in cellular environment.

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Abstract 2133: Systematic mapping of genetic interactions in human cancer cells reveals context dependent cancer signaling pathways

10.1158/1538-7445.am2021-2133 ◽

2021 ◽

Author(s):

Samson H. Fong ◽

Brent M. Kuenzi ◽

John Lee ◽

Kyle Sanchez ◽

Ana Bojorquez-Gomez ◽

...

Keyword(s):

Cancer Cells ◽

Signaling Pathways ◽

Human Cancer ◽

Genetic Interactions ◽

Systematic Mapping ◽

Human Cancer Cells ◽

Cancer Signaling ◽

Context Dependent

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WEE1 inhibition in pancreatic cancer cells is dependent on DNA repair status in a context dependent manner

Scientific Reports ◽

10.1038/srep33323 ◽

2016 ◽

Vol 6 (1) ◽

Cited By ~ 19

Author(s):

Shruti Lal ◽

Mahsa Zarei ◽

Saswati N. Chand ◽

Emanuela Dylgjeri ◽

Nicole C. Mambelli-Lisboa ◽

...

Keyword(s):

Pancreatic Cancer ◽

Dna Repair ◽

Cancer Cells ◽

Dependent Manner ◽

Pancreatic Cancer Cells ◽

Context Dependent

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VER-246608, a novel pan-isoform ATP competitive inhibitor of pyruvate dehydrogenase kinase, disrupts Warburg metabolism and induces context-dependent cytostasis in cancer cells

Oncotarget ◽

10.18632/oncotarget.2656 ◽

2014 ◽

Vol 5 (24) ◽

pp. 12862-12876 ◽

Cited By ~ 28

Author(s):

Jonathan D. Moore ◽

Anna Staniszewska ◽

Terence Shaw ◽

Jalanie D’Alessandro ◽

Ben Davis ◽

...

Keyword(s):

Cancer Cells ◽

Pyruvate Dehydrogenase ◽

Competitive Inhibitor ◽

Pyruvate Dehydrogenase Kinase ◽

Context Dependent

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Context-dependent activation of SIRT3 is necessary for anchorage-independent survival and metastasis of ovarian cancer cells

10.1101/670778 ◽

2019 ◽

Author(s):

Yeon Soo Kim ◽

Piyushi Gupta-Vallur ◽

Victoria M. Jones ◽

Beth L. Worley ◽

Sara Shimko ◽

...

Keyword(s):

Ovarian Cancer ◽

Cancer Cells ◽

Tumor Cells ◽

Peritoneal Cavity ◽

Antioxidant Defenses ◽

Ovarian Cancer Cells ◽

Dependent Manner ◽

Anoikis Resistance ◽

Primary Tumors ◽

Context Dependent

ABSTRACTCells must alter their antioxidant capacity for maximal metastatic potential. However, the antioxidant adaptations required for transcoelomic metastasis, which is the passive dissemination of cancer cells in the peritoneal cavity as seen in ovarian cancer, have largely remained unexplored. Contradicting the need for oxidant scavenging by tumor cells is the observation that expression of the nutrient stress sensor and regulator of mitochondrial antioxidant defenses, SIRT3, is suppressed in many primary tumors. We discovered that this mitochondrial deacetylase is however, upregulated in a context-dependent manner in cancer cells. SIRT3 activity and expression transiently increased following ovarian cancer cell detachment and in tumor cells derived from malignant ascites of high-grade serous adenocarcinoma patients. Mechanistically, SIRT3 prevents mitochondrial superoxide surges in detached cells by regulating the manganese superoxide dismutase SOD2. This mitochondrial stress response is under dual regulation by SIRT3. SIRT3 rapidly increases SOD2 activity as an early adaptation to cellular detachment, which is followed by SIRT3-dependent transcriptional increases in SOD2 during sustained anchorage-independence. In addition, SIRT3 inhibits glycolytic capacity in anchorage-independent cells thereby contributing to metabolic changes in response to detachment. While manipulation of SIRT3 expression has few deleterious effects on cancer cells in attached conditions, SIRT3 up-regulation and SIRT3-mediated oxidant scavenging following matrix detachment are required for anoikis resistance in vitro, and both SIRT3 and SOD2 are necessary for colonization of the peritoneal cavity in vivo. Our results highlight the novel context-specific, pro-metastatic role of SIRT3 in ovarian cancer.

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Context-dependent activation of SIRT3 is necessary for anchorage-independent survival and metastasis of ovarian cancer cells

Oncogene ◽

10.1038/s41388-019-1097-7 ◽

2019 ◽

Vol 39 (8) ◽

pp. 1619-1633 ◽

Cited By ~ 1

Author(s):

Yeon Soo Kim ◽

Piyushi Gupta Vallur ◽

Victoria M. Jones ◽

Beth L. Worley ◽

Sara Shimko ◽

...

Keyword(s):

Ovarian Cancer ◽

Cancer Cells ◽

Ovarian Cancer Cells ◽

Context Dependent

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Mps1 expression is critical for chromosome orientation and segregation in yeast with high ploidy

10.1101/2020.03.26.006387 ◽

2020 ◽

Author(s):

Ashlea Sartin ◽

Madeline Gish ◽

Jillian Harsha ◽

Dawson Haworth ◽

Rebecca LaVictoire ◽

...

Keyword(s):

Cell Division ◽

Chromosome Number ◽

Cancer Cells ◽

Chromosome Segregation ◽

Daughter Cell ◽

Yeast Cells ◽

Loss Of Function ◽

Master Regulator ◽

High Ploidy ◽

Mutant Cells

AbstractIn aneuploid cancer cells, the chromosome segregation apparatus is sensitive to increased chromosome number. The conserved protein kinase, Mps1, is a critical actor of this machinery, orienting the chromosomes properly on the spindle. Abnormally high levels of this kinase have been found in tumors with elevated chromosome number. However, it remains unclear, mechanistically, if and how cells with higher ploidy become dependent upon increased Mps1 levels. To answer these questions, we explored Mps1 dependence in yeast cells with increased sets of chromosomes. We discovered that having more chromosomes affects the ability of cells to orient chromosomes properly. The cells with increased numbers of chromosomes are particularly sensitive to the reduction of Mps1 activity. In mps1 loss of function mutants, cells display an extended prometaphase with a longer spindle and a delay in orienting properly the chromosomes. Altogether, our results suggest that increased numbers of chromosomes render cells more dependent on Mps1 for orienting chromosomes on the spindle. The phenomenon described here may be relevant in understanding why hyperdiploid cancer cells become excessively reliant on high Mps1 expression for successful chromosome segregation.Author summaryMost cells in solid tumors usually carry far more chromosomes than normal cells. Losing or gaining chromosomes during cell division can lead to aneuploidy (an abnormal number of chromosomes), cancer, and other diseases. Mps1 is a master regulator of cell division that is critical to keep the correct number chromosomes in each daughter cell. This master regulator has been shown to target and affect the function of various actors involved in cell division. Abnormally high levels of this master regulator are found in tumors with elevated chromosome numbers. The high levels of this regulator appear to be protecting these tumor cells. To answer if and how cells with higher ploidy become so dependent of Mps1, we generated yeast cells with increased set of chromosomes. Here, we report that cells with elevated chromosome number are particularly sensitive to the reduction of Mps1 level. In cells with higher ploidy and reduced level of Mps1, the progression during cell division is delayed. In the mutant cells, their ability to properly orient and segregate their chromosomes on the spindle is greatly reduced.

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