Malignant peritoneal mesothelioma interactome with 417 novel protein-protein interactions

Our plain-English summary of Malignant peritoneal mesothelioma interactome with 417 novel protein-protein interactions, by K.B. Karunakaran, M.K. Ganapathiraju (BJC Reports, 2024).

The study

• Authors: K.B. Karunakaran, M.K. Ganapathiraju
• Journal: BJC Reports
• Published: 2024;2(1):42
• Cited by: 2 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Malignant peritoneal mesothelioma (MPeM) is an aggressive cancer affecting the abdominal peritoneal lining and intra-abdominal organs, with a median survival of ~2.5 years.

Methods: We constructed the protein interactome of 59 MPeM-associated genes with previously known protein-protein interactions (PPIs) as well as novel PPIs predicted using our previously developed HiPPIP computational model and analysed it for transcriptomic and functional associations and for repurposable drugs.

Results: The MPeM interactome had over 400 computationally predicted PPIs and 4700 known PPIs. Transcriptomic evidence validated 75.6% of the genes in the interactome and 65% of the novel interactors. Some genes had tissue-specific expression in extramedullary hematopoietic sites and the expression of some genes could be correlated with unfavourable prognoses in various cancers. 39 out of 152 drugs that target the proteins in the interactome were identified as potentially repurposable for MPeM, with 29 having evidence from prior clinical trials, animal models or cell lines for effectiveness against peritoneal and pleural mesothelioma and primary peritoneal cancer. Functional modules related to chromosomal segregation, transcriptional dysregulation, IL-6 production and hematopoiesis were identified from the interactome. The MPeM interactome overlapped significantly with the malignant pleural mesothelioma interactome, revealing shared molecular pathways.

Conclusions: Our findings demonstrate the utility of the interactome in uncovering biological associations and in generating clinically translatable results.

© 2024. The Author(s).

In plain English

This was a computer-based (bioinformatics) study. It did not examine patients directly. The authors took 59 genes that earlier published studies had linked to malignant peritoneal mesothelioma (MPeM), a cancer of the abdominal lining. They built a map of the proteins these genes interact with, combining interactions already listed in databases with new ones predicted by their own computer model, HiPPIP. The map contained 4747 known and 417 predicted new interactions, linking 58 of the genes to 2747 known and 306 new partner proteins. Of the 306 new partners, 198 (65%) showed changes in gene activity in data from peritoneal mesothelioma tumours, animal models, or mesothelial cells exposed to crocidolite asbestos in the laboratory; so did 2353 (75.6%) of all proteins in the map. The map shared 989 genes with the authors' earlier map for pleural mesothelioma. Of 152 drugs acting on proteins in the map, 39 were flagged as possibly reusable for MPeM, and the authors' literature review supported 29 of them. The authors said some analyses relied on animal data and that their conclusions need laboratory confirmation.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Computational (bioinformatics) protein-protein interaction network ('interactome') analysis; described by the authors as exploratory
• Who was studied: No new patients. Subjects were 59 MPeM-associated genes compiled from previously published genetic studies of MPeM patient samples (Table 1 lists nine studies), plus public gene-expression datasets from peritoneal mesothelioma tumours, rodent models and mesothelial cell lines
• Exposure: Asbestos exposure was not studied in people. Among the gene-expression datasets compared with the interactome were mouse peritoneal mesothelioma cell lines resulting from crocidolite asbestos, human peritoneal mesothelial cell lines exposed to crocidolite, and lungs of mice exposed to crocidolite or wollastonite fibres
• Main results:
  • The MPeM interactome contained 4747 known and 417 novel (computer-predicted) protein-protein interactions, connecting 58 MPeM-associated genes to 2747 known and 306 novel interactors; the 59th gene, ADAM3A, had no interactions
  • 198 of 306 (65%) novel interactors, and 2353 (75.6%) proteins overall, showed differential gene expression in pre-clinical models and human tumour specimens of peritoneal mesothelioma
  • Overlaps with rat models of spontaneous and chemically induced peritoneal mesothelioma were not statistically significant
  • The interactome was significantly enriched for genes differentially expressed in biphasic peritoneal mesothelioma, but not in epithelial peritoneal mesothelioma
  • The interactome was enriched in human counterparts of mouse genes specific to spleen (81 genes, P-value = 0.019, odds ratio = 1.39) and thymus (57 genes, P-value = 0.028, odds ratio = 1.42); only 6 genes showed peritoneum-specific expression
  • The MPeM interactome shared 989 genes with the authors' earlier malignant pleural mesothelioma interactome (P-value = 3.18E−289, odds ratio = 2.92)
  • 152 drugs from Drug Bank targeted 427 interactome proteins; 39 were identified as potentially repurposable for MPeM, and the authors' literature review supported the biological validity of 29 (74%) of these 39
• The authors' conclusion: The authors concluded that the study gives a network-level view of MPeM-associated genes and their functional consequences, and that the hypotheses it generates can be tested further in laboratory and animal studies
• Limitations the authors state:
  • Several analyses used genetic data from animal models because human patient data were absent, so those results should be interpreted with caution
  • The bioinformatics-based conclusions need experimental confirmation in relevant tissues or cell lines
  • The drug-induced expression profiles came from a wide variety of cell lines, so the shortlisted drugs should be tested in human peritoneal mesothelioma cell lines or animal models

Topics

Medical terms in this study, explained in our Lexicon: Peritoneal Mesothelioma, Median Overall Survival, Clinical Trial, Pleural Mesothelioma.

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