Extensive protein dosage compensation in aneuploid human cancers

Mapping Intimacies ◽

10.1101/2021.06.18.449005 ◽

2021 ◽

Author(s):

Klaske Marijke Schukken ◽

Jason Meyer Sheltzer

Keyword(s):

Protein Expression ◽

Dosage Compensation ◽

Copy Number ◽

Human Cancer ◽

Tumor Development ◽

Driver Genes ◽

Human Cancer Cell Lines ◽

Chromosome Copy Number ◽

Human Cancers ◽

Copy Number Changes

Aneuploidy is a hallmark of human cancers, but the effects of aneuploidy on protein expression remain poorly understood. To uncover how chromosome copy number changes influence the cancer proteome, we have conducted an analysis of hundreds of human cancer cell lines with matched copy number, RNA expression, and protein expression data. We found that a majority of proteins exhibit dosage compensation and fail to change by the degree expected based on chromosome copy number alone. We uncovered a variety of gene groups that were recurrently buffered upon both chromosome gain and loss, including protein complex subunits and cell cycle genes. Several genetic and biophysical factors were predictive of protein buffering, highlighting complex post-translational regulatory mechanisms that maintain appropriate gene product dosage. Finally, we established that chromosomal aneuploidy has an unexpectedly moderate effect on the expression of oncogenes and tumor suppressors, demonstrating that these key cancer drivers can be subject to dosage compensation as well. In total, our comprehensive analysis of aneuploidy and dosage compensation across cancers will help identify the key driver genes encoded on altered chromosomes and will shed light on the overall consequences of aneuploidy during tumor development.

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Multi-omics approach to infer cancer therapeutic targets on chromosome 20q across tumor types

Advances in Modern Oncology Research ◽

10.18282/amor.v2.i4.141 ◽

2016 ◽

Vol 2 (4) ◽

pp. 215 ◽

Cited By ~ 2

Author(s):

Antoine M Snijders ◽

Jian-Hua Mao

Keyword(s):

Copy Number ◽

Human Cancer ◽

The Cancer Genome Atlas ◽

Integrated Analysis ◽

Dna Copy Number ◽

Driver Genes ◽

Major Mechanism ◽

Normal Tissues ◽

Human Cancers ◽

Tumor Types

<p>The identification of good targets is a critical step for the development of targeted therapies for cancer treatment. Here, we used a multi-omics approach to delineate potential targets on chromosome 20q, which frequently shows a complex pattern of DNA copy number amplification in many human cancers suggesting the presence of multiple driver genes. By comparing the amounts of individual mRNAs in cancer from 11 different human tissues with those in their corresponding normal tissues, we identified 18 genes that were robustly elevated across human cancers. Moreover, we found that higher expression levels of a majority of these genes were associated with poor prognosis in many human cancer types. Using DNA copy number and expression data for all 18 genes obtained from The Cancer Genome Atlas project, we discovered that amplification is a major mechanism driving overexpression of these 18 genes in the majority of human cancers. Our integrated analysis suggests that 18 genes on chromosome 20q might serve as novel potential molecular targets for targeted cancer therapy.</p>

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AKT1-CREB stimulation of PDGFRα expression is pivotal for PTEN deficient tumor development

Cell Death and Disease ◽

10.1038/s41419-021-03433-0 ◽

2021 ◽

Vol 12 (2) ◽

Author(s):

Xiaofeng Wan ◽

Meng Zhou ◽

Fuqiang Huang ◽

Na Zhao ◽

Xu Chen ◽

...

Keyword(s):

Signaling Pathway ◽

Human Cancer ◽

Critical Role ◽

Tumor Development ◽

Growth Factor Receptor ◽

Conditional Knockout ◽

Loss Of Function ◽

Akt Inhibitor ◽

Human Cancer Cell Lines ◽

Direct Binding

AbstractAs evidenced by the behavior of loss-of-function mutants of PTEN in the context of a gain-of-function mutation of AKT1, the PTEN-AKT1 signaling pathway plays a critical role in human cancers. In this study, we demonstrated that a deficiency in PTEN or activation of AKT1 potentiated the expression of platelet-derived growth factor receptor α (PDGFRα) based on studies on Pten−/− mouse embryonic fibroblasts, human cancer cell lines, the hepatic tissues of Pten conditional knockout mice, and human cancer tissues. Loss of PTEN enhanced PDGFRα expression via activation of the AKT1-CREB signaling cascade. CREB transactivated PDGFRα expression by direct binding of the promoter of the PDGFRα gene. Depletion of PDGFRα attenuated the tumorigenicity of Pten-null cells in nude mice. Moreover, the PI3K-AKT signaling pathway has been shown to positively correlate with PDGFRα expression in multiple cancers. Augmented PDGFRα was associated with poor survival of cancer patients. Lastly, combination treatment with the AKT inhibitor MK-2206 and the PDGFR inhibitor CP-673451 displayed synergistic anti-tumor effects. Therefore, activation of the AKT1-CREB-PDGFRα signaling pathway contributes to the tumor growth induced by PTEN deficiency and should be targeted for cancer treatment.

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Array rank order regression analysis for the detection of gene copy-number changes in human cancer

Genomics ◽

10.1016/s0888-7543(03)00122-8 ◽

2003 ◽

Vol 82 (2) ◽

pp. 122-129 ◽

Cited By ~ 16

Author(s):

Chun Cheng ◽

Robert Kimmel ◽

Paul Neiman ◽

Lue Ping Zhao

Keyword(s):

Regression Analysis ◽

Copy Number ◽

Human Cancer ◽

Rank Order ◽

Gene Copy Number ◽

Gene Copy ◽

Copy Number Changes

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Abstract 5759: The landscape of copy-number changes across multiple human cancer types

10.1158/1538-7445.am10-5759 ◽

2010 ◽

Cited By ~ 1

Author(s):

Rameen Beroukhim ◽

Matthew Meyerson ◽

Levi Garraway ◽

John Prensner

Keyword(s):

Copy Number ◽

Human Cancer ◽

Cancer Types ◽

Copy Number Changes

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Abstract 2993: Comparison of copy number variation using exome sequencing and affymetrix SNP6.0 genotype array in human cancer cell lines

10.1158/1538-7445.am2012-2993 ◽

2012 ◽

Author(s):

Jian Wang ◽

Thompson N. Doman ◽

Xiwen Ma ◽

Dan S. Li ◽

Amit Aggarwal ◽

...

Keyword(s):

Copy Number Variation ◽

Exome Sequencing ◽

Cell Lines ◽

Cancer Cell ◽

Copy Number ◽

Human Cancer ◽

Human Cancer Cell ◽

Human Cancer Cell Lines ◽

Number Variation ◽

Genotype Array

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Effect of GHRH and peptides from the vasoactive intestinal peptide family on cAMP production of human cancer cell lines in vitro

Journal of Endocrinology ◽

10.1677/joe.0.1630269 ◽

1999 ◽

Vol 163 (2) ◽

pp. 269-280 ◽

Cited By ~ 11

Author(s):

V Csernus ◽

AV Schally ◽

K Groot

Keyword(s):

Adenylate Cyclase ◽

Vasoactive Intestinal Peptide ◽

Cell Lines ◽

Cancer Cell ◽

Human Cancer ◽

Cancer Cell Lines ◽

Human Cancer Cell ◽

Human Cancer Cell Lines ◽

Human Cancers

Antagonistic analogs of GHRH inhibit growth of various human cancers both in vivo and in vitro. To elucidate the mechanism of direct action of the antagonistic analogs of GHRH on tumor cells, cultured human cancer cells were exposed to GHRH, vasoactive intestinal peptide (VIP), secretin, glucagon, neuropeptide-Y (NPY), pituitary adenylate cyclase-activating peptide (PACAP), and VIP analogs in a superfusion system, and changes in cAMP and IGF-II release from the cells were measured. Various human cancer cell lines, such as mammary (MDAMB-468 and ZR-75-1), prostatic (PC-3), pancreatic (SW-1990 and Capan-2), ovarian (OV-1063), and colorectal (LoVo) responded to pulsatile stimuli with GHRH (0.5-20 nM), VIP (0.02-10 nM), and PACAP-38 (0.05-5 nM) with a rapid, transient increase in cAMP release from the cells. The VIP antagonist, PG-97-269, and the adenylate cyclase inhibitor, MDL-12330A, but not SQ-22536 or pertussis toxin, blocked the cAMP responses to these peptides. Stimulation of the cells with 100 nM secretin, glucagon or NPY did not alter the cAMP release. Our results suggest that GHRH receptors different from the type expressed in the pituitary are involved in mediating these effects. As cAMP is a potent second messenger controlling a wide variety of intracellular functions, including those required for cell growth, our results indicate that GHRH might have a direct stimulatory effect on growth of human cancers. Blockade of the autocrine/paracrine action of GHRH with its antagonistic analogs may provide a new approach to tumor control.

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Functional linkage of gene fusions to cancer cell fitness assessed by pharmacological and CRISPR/Cas9 screening

10.1101/559690 ◽

2019 ◽

Author(s):

Gabriele Picco ◽

Elisabeth D Chen ◽

Luz Garcia Alonso ◽

Fiona M Behan ◽

Emanuel Gonçalves ◽

...

Keyword(s):

Tumor Cell ◽

Cancer Cell ◽

Human Cancer ◽

Drug Repurposing ◽

Gene Fusions ◽

Sequencing Data ◽

Multiple Cancer ◽

Driver Genes ◽

Systematic Analysis ◽

Human Cancer Cell Lines

AbstractMany gene fusions have been reported in tumours and for most their role remains unknown. As fusions can be used clinically for diagnostic and prognostic purposes, and are targets for treatment, it is crucial to assess their functional implications in cancer. To investigate the role of fusions in tumor cell fitness, we developed a systematic analysis utilising RNA-sequencing data from 1,011 human cancer cell lines to functionally link 8,354 gene fusion events with genomic data, sensitivity to >350 anti-cancer drugs and CRISPR-Cas9 loss-of-fitness information. Established clinically-relevant fusions were readily identified. Overall, functional fusions were rare, including those involving cancer driver genes, suggesting that many fusions are dispensable for tumor cell fitness. Novel therapeutically actionable fusions involving RAF1, BRD4 and ROS1 were verified in new histologies. In addition, recurrent YAP1-MAML2 fusions were identified as activators of Hippo-pathway signaling in multiple cancer types, supporting therapeutic targeting of Hippo signalling. Our approach discriminates functional fusions, identifying new drivers of carcinogenesis and fusions that could have important clinical implications.SignificanceWe identify fusions as new potential candidates for drug repurposing and drivers of carcinogenesis. These results support histology agnostic marker-driven precision cancer medicine. Most fusions are not functional with implications for interpreting cancer fusions reported from clinical sequencing studies.

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