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Disruption of cancer cell functions by task-specific drug perturbations.

ABSTRACT: Cancer expands clonally, capitalizing on the variations between growing cells. Cancer cells specialize in one or more functions to gain an advantage. This study examined the prediction that cells would be vulnerable to drugs that perturb their specific tasks. We analyzed the correlation between gene expression and the response to drug perturbations in different cancer cells. Next, we assigned every cancer cell to an archetype based on gene expression. Finally, we calculated the enrichment of the cancer hallmark gene sets in each cell, archetypes, and response to drug treatment. We found that the extremes of gene expression were susceptible to change in response to perturbations. This correlation predicted the growth rate inhibition of breast cancer cells. Cancer hallmarks were enriched differently in the archetypes, and this enrichment predicted the cell's response to perturbations. We present evidence that specialized cancer cells are sensitive to compounds that perturb their tasks.

SUBMITTER: Ahmed M

PROVIDER: S-EPMC9386472 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Disruption of cancer cell functions by task-specific drug perturbations.

Ahmed Mahmoud M Kim Deok Ryong DR

Frontiers in pharmacology 20220804

Cancer expands clonally, capitalizing on the variations between growing cells. Cancer cells specialize in one or more functions to gain an advantage. This study examined the prediction that cells would be vulnerable to drugs that perturb their specific tasks. We analyzed the correlation between gene expression and the response to drug perturbations in different cancer cells. Next, we assigned every cancer cell to an archetype based on gene expression. Finally, we calculated the enrichment of the ...[more]

PMID: 35991905

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Project description:BackgroundRenal cell carcinoma (RCC) is a complex disease and is comprised of several histological subtypes, the most frequent of which are clear cell renal cell carcinoma (ccRCC), papillary renal cell carcinoma (PRCC) and chromophobe renal cell carcinoma (ChRCC). While lots of studies have been performed to investigate the molecular characterizations of different subtypes of RCC, our knowledge regarding the underlying mechanisms are still incomplete. As molecular alterations are eventually reflected on the pathway level to execute certain biological functions, characterizing the pathway perturbations is crucial for understanding tumorigenesis and development of RCC.MethodsIn this study, we investigated the pathway perturbations of various RCC subtype against normal tissue based on differential expressed genes within a certain pathway. We explored the potential upstream regulators of subtype-specific pathways with Ingenuity Pathway Analysis (IPA). We also evaluated the relationships between subtype-specific pathways and clinical outcome with survival analysis.ResultsIn this study, we carried out a pathway-based analysis to explore the mechanisms of various RCC subtypes with TCGA RNA-seq data. Both commonly altered pathways and subtype-specific pathways were detected. To identify the distinctive characteristics of each subtype, we focused on subtype-specific perturbed pathways. Specifically, we observed that some of the altered pathways were regulated by several recurrent upstream regulators which presenting different expression patterns among distinct RCC subtypes. We also noticed that a large number of perturbed pathways were controlled by the subtype-specific upstream regulators. Moreover, we also evaluated the relationships between perturbed pathways and clinical outcome. Prognostic pathways were identified and their roles in tumor development and progression were inferred.ConclusionsIn summary, we evaluated the relationships among pathway perturbations, upstream regulators and clinical outcome for differential subtypes in RCC. We hypothesized that the alterations of common upstream regulators as well as subtype-specific upstream regulators work together to affect the downstream pathway perturbations and drive cancer initialization and prognosis. Our findings not only increase our understanding of the mechanisms of various RCC subtypes, but also provide targets for personalized therapeutic intervention.

Dataset Information

Disruption of cancer cell functions by task-specific drug perturbations.

Publications

Disruption of cancer cell functions by task-specific drug perturbations.

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