Regulation of protein complex partners as a compensatory mechanism in aneuploid tumors
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Evaluation Summary:
This paper will be of interest to the cancer biology community. The study leverages high-throughput genomic and proteomic data to evaluate the role of aneuploidy on functional pathway changes in cancer.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1, Reviewer #2 and Reviewer #3 agreed to share their name with the authors.)
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Abstract
Aneuploidy, a state of chromosome imbalance, is a hallmark of human tumors, but its role in cancer still remains to be fully elucidated. To understand the consequences of whole-chromosome-level aneuploidies on the proteome, we integrated aneuploidy, transcriptomic, and proteomic data from hundreds of The Cancer Genome Atlas/Clinical Proteomic Tumor Analysis Consortium tumor samples. We found a surprisingly large number of expression changes happened on other, non-aneuploid chromosomes. Moreover, we identified an association between those changes and co-complex members of proteins from aneuploid chromosomes. This co-abundance association is tightly regulated for aggregation-prone aneuploid proteins and those involved in a smaller number of complexes. On the other hand, we observed that complexes of the cellular core machinery are under functional selection to maintain their stoichiometric balance in aneuploid tumors. Ultimately, we provide evidence that those compensatory and functional maintenance mechanisms are established through post-translational control, and that the degree of success of a tumor to deal with aneuploidy-induced stoichiometric imbalance impacts the activation of cellular protein degradation programs and patient survival.
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Evaluation Summary:
This paper will be of interest to the cancer biology community. The study leverages high-throughput genomic and proteomic data to evaluate the role of aneuploidy on functional pathway changes in cancer.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1, Reviewer #2 and Reviewer #3 agreed to share their name with the authors.)
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Reviewer #1 (Public Review):
This manuscript leverages large scale cancer genomics and proteomics datasets from the Cancer Genome Atlas Project to evaluate the association between aneuploidy and protein structure / function in cancer. They perform a comprehensive multi-omics analysis to look at regulatory mechanisms.
This represents a comprehensive analysis across all different data modalities. They perform a comprehensive analysis of proteomics data, particularly novel for evaluation of protein structure and regulation and its association with aneuploidy.
Some of the other analyses, e.g., gene expression, DNA methylation, survival, could benefit from additional expansion.
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Reviewer #2 (Public Review):
Aneuploidies, loss or gain of chromosomes of chromosome arms, are very common in cancer with up to 90% of tumors displaying these types of major chromosomal aberrations. Since certain types of aneuploidies are commonly recurrent in different types of cancers it's widely assumed that they give certain advantages to the cancer - e.g., by increasing the abundance of oncogenes or perhaps decreasing the abundance of tumor suppressor genes. However, these types of large-scale changes in gene dosage also cause issues for the cancer cell as all genes encoded on the aneuploid chromosomes become over or under-expressed.
The consequences of aneuploidy on gene expression have been studied, most commonly using cell lines or in yeast, and it has been found that RNA levels usually scale with the aneuploidy. For example, in …
Reviewer #2 (Public Review):
Aneuploidies, loss or gain of chromosomes of chromosome arms, are very common in cancer with up to 90% of tumors displaying these types of major chromosomal aberrations. Since certain types of aneuploidies are commonly recurrent in different types of cancers it's widely assumed that they give certain advantages to the cancer - e.g., by increasing the abundance of oncogenes or perhaps decreasing the abundance of tumor suppressor genes. However, these types of large-scale changes in gene dosage also cause issues for the cancer cell as all genes encoded on the aneuploid chromosomes become over or under-expressed.
The consequences of aneuploidy on gene expression have been studied, most commonly using cell lines or in yeast, and it has been found that RNA levels usually scale with the aneuploidy. For example, in yeast an extra chromosome in a monosomic strain leads to a 100% increase of mRNA encoded on the disomic chromosome. This 100% increase, mainly, holds true also at the protein level. However around 20% of proteins remain at baseline levels even though their mRNA levels are elevated, a phenomenon labeled attenuation. These attenuated proteins were found to be enriched for protein complex subunits, leading to the idea that stoichiometric assembly followed by degradation of orphaned (overexpressed) subunits causes the attenuation of the overexpressed subunits. At least in yeast, little translational feedback has been shown during aneuploidy, while increased degradation as well as aggregation of overexpressed and orphaned subunits have been directly measured, lending credence to this mechanism. Thus, the consequences of aneuploidy on the directly affected chromosomes are known to some extent. However, an important question that has yet to be answered is: What are the consequences of aneuploidy on gene expression of diploid chromosomes?
Here, Senger and colleagues leverage the massive transcriptomic and proteomic data sets generated by The Cancer Genome Atlas Project (TCGA) and Clinical Proteomic Tumor Analysis Consortium (CPTAC) to not only shed light on the in vivo effects of aneuploidy on gene expression in primary tumors but also the consequences of aneuploidy on the diploid chromosomes. The authors find that once again protein complex subunits play a special role as the abundance of complex subunits encoded on diploid chromosomes tend to scale with their interaction partners on the aneuploid chromosomes. Further, the authors show that the proteins complex subunits encoded on diploid chromosomes that are most likely to be impacted by their interaction partners partake in relatively fewer complexes and are more aggregation prone. This the authors argue is to prevent the accumulation and aggregation of orphan subunits in cancer. Finally, they show that cancers that manage to correlate the expression of protein complex subunit genes between aneuploid and diploid chromosomes, have less upregulated proteasomes and importantly are related to lower survival probability in patients.
The manuscript is well written and argued and is a great example of how analyzing large public dataset can reveal important findings. They find a strong and believable link between differentially abundant proteins encoded on diploid chromosomes and differentially abundant proteins encoded on aneuploid chromosomes. E.g. around 40% of differentially expressed genes in COREAD are interaction partners with proteins differentially expressed genes on the amplified chromosome 7. In addition, the authors convincingly show that subunits that are less promiscuous and more aggregation prone drive the up regulation of interaction partners encoded on non-aneuploid chromosomes. Interestingly, the authors also show that cancers that effectively manage their aneuploidies by stoichiometrically upregulating interaction partners encoded on non-aneuploid chromosomes have a proliferation advantage and are associated with a worse outcome for patients. Some conclusions drawn in this manuscript I find a bit less well supported, although still interesting, such as the functional analysis in Figure 4 and the ubiquitin analysis in Figure 5. Overall, I think this manuscript is a great addition to the field.
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Reviewer #3 (Public Review):
Aneuploidy, a state of whole- or arm-level chromosomal alterations, is detrimental in normal cells due to gene expression imbalance, but paradoxically it is a hallmark of cancer cells. A long-standing question has been how do cancer cells tolerate aneuploidy. In this study, the authors used elegant bioinformatic analyses integrating karyotypic, transcriptomic and proteomic data from hundreds of tumor samples to tackle this question. Extending the scope of previous findings suggesting post-transcriptional regulation as a dosage compensation mechanism in response to aneuploidy/CNAs, this study specifically focuses on the effects on non-aneuploid chromosomes, which have remained elusive at the proteome level. Proteins encoded by the non-aneuploid chromosomes found to be differentially abundant in aneuploid …
Reviewer #3 (Public Review):
Aneuploidy, a state of whole- or arm-level chromosomal alterations, is detrimental in normal cells due to gene expression imbalance, but paradoxically it is a hallmark of cancer cells. A long-standing question has been how do cancer cells tolerate aneuploidy. In this study, the authors used elegant bioinformatic analyses integrating karyotypic, transcriptomic and proteomic data from hundreds of tumor samples to tackle this question. Extending the scope of previous findings suggesting post-transcriptional regulation as a dosage compensation mechanism in response to aneuploidy/CNAs, this study specifically focuses on the effects on non-aneuploid chromosomes, which have remained elusive at the proteome level. Proteins encoded by the non-aneuploid chromosomes found to be differentially abundant in aneuploid tumors, mainly complex with proteins encoded by the aneuploid chromosome. In amplifications, this dosage compensation primarily affects complex partners of aggregation-prone, non-promiscuous aneuploid proteins. In deletions, differentially abundant proteins encoded by the non-aneuploid chromosomes are mainly complex partners involved in essential cell function processes. Both the compensatory and functional maintenance mechanisms are shown to be regulated at the post-transcriptional level. Aneuploid tumors with higher post-transcriptional control of co-complex members of aneuploid proteins were found to associate with poor patient survival suggesting their improved fitness/adaptation to stoichiometric imbalance. These data add to the elucidation of the paradoxical role of aneuploidy in cancer. The conclusions of this paper are mostly well supported by the data, but interpretation of the results can be further improved.
Major comments:
The data in Fig. 1C interestingly shows that only 41-48% of the transcripts encoded by the aneuploid chromosomes are altered. This suggests that transcriptional control appears as a major determinant of gene dosage compensation for the aneuploid chromosome, whereas post-transcriptional regulation could predominate for the non-aneuploid chromosomes.
Still related to Fig. 1C, perhaps is misleading to show the transcriptome and proteome data in the same graphs. The transcriptome data appears to be from 32 cancer types, whereas the proteome data are from 3 cancer types as mentioned in page 6. The authors should provide in Fig. 1 the graphs of transcriptome and proteome comparative analysis in the COREAD, BRCA and OV cancer types only. This would be useful to address the questions below (see point 3).
Then, it would be important to crosstalk the transcriptome and proteome data to determine:
- If the proteome changes primarily include genes altered at the transcriptome level or not;
- If there is gene overlapping in the transcriptional and proteomic changes seen for the other chromosomes, which percentages are interestingly similar.As mentioned in page 10, in the case of chromosomal deletions the aggregation propensity of downregulated proteins on the aneuploid chromosome should not affect the degree of correlation with complex partners. But did the authors consider investigating if the complex partners on other chromosomes, in the case of deletions, are aggregation-prone?
This would mean that post-transcriptional regulation of partner co-abundance might operate in both amplifications and deletions, as well as functional selection apparently.Regarding the phenotypic consequences of stoichiometric compensation proficiency, a correlation is shown in Fig. 6 between lower stoichiometry deviation score and poorer survival. Tumors with higher stoichiometry deviation score correlate with higher abundance of proteins involved in protein degradation. Do these correlations still apply if the tumors' samples are separated in amplification and deletion groups?
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