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Somatic mutations in early metazoan genes disrupt regulatory links between unicellular and multicellular genes in cancer.

ABSTRACT: Extensive transcriptional alterations are observed in cancer, many of which activate core biological processes established in unicellular organisms or suppress differentiation pathways formed in metazoans. Through rigorous, integrative analysis of genomics data from a range of solid tumors, we show many transcriptional changes in tumors are tied to mutations disrupting regulatory interactions between unicellular and multicellular genes within human gene regulatory networks (GRNs). Recurrent point mutations were enriched in regulator genes linking unicellular and multicellular subnetworks, while copy-number alterations affected downstream target genes in distinctly unicellular and multicellular regions of the GRN. Our results depict drivers of tumourigenesis as genes that created key regulatory links during the evolution of early multicellular life, whose dysfunction creates widespread dysregulation of primitive elements of the GRN. Several genes we identified as important in this process were associated with drug response, demonstrating the potential clinical value of our approach.

SUBMITTER: Trigos AS

PROVIDER: S-EPMC6402835 | biostudies-other | 2019 Feb

REPOSITORIES: biostudies-other

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Somatic mutations in early metazoan genes disrupt regulatory links between unicellular and multicellular genes in cancer.

Trigos Anna S AS Pearson Richard B RB Papenfuss Anthony T AT Goode David L DL

eLife 20190226

Extensive transcriptional alterations are observed in cancer, many of which activate core biological processes established in unicellular organisms or suppress differentiation pathways formed in metazoans. Through rigorous, integrative analysis of genomics data from a range of solid tumors, we show many transcriptional changes in tumors are tied to mutations disrupting regulatory interactions between unicellular and multicellular genes within human gene regulatory networks (GRNs). Recurrent poin ...[more]

PMID: 30803482

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Project description:Mechanical stress patterns emerging from collective cell behavior have been shown to play critical roles in morphogenesis, tissue repair, and cancer metastasis. In our previous work, we constrained valvular interstitial cell (VIC) monolayers on circular protein islands to study emergent behavior in a controlled manner and demonstrated that the general patterns of cell alignment, size, and apoptosis correlate with predicted mechanical stress fields if radially increasing stiffness or contractility are used in the computational models. However, these radially symmetric models did not predict the existence of local regions of dense aligned cells observed in seemingly random locations of individual aggregates. The goal of this study is to determine how the heterogeneities in cell behavior emerge over time and diverge from the predicted collective cell behavior. Cell-cell interactions in circular multicellular aggregates of VICs were studied with time-lapse imaging ranging from hours to days, and migration, proliferation, and traction stresses were measured. Our results indicate that elongated cells create strong local alignment within preconfluent cell populations on the microcontact printed protein islands. These cells influence the alignment of additional cells to create dense, locally aligned bands of cells which disrupt the predicted global behavior. Cells are highly elongated at the endpoints of the bands yet have decreased spread area in the middle and reduced mobility. Although traction stresses at the endpoints of bands are enhanced, even to the point of detaching aggregates from the culture surface, the cells in dense bands exhibit reduced proliferation, less nuclear YAP, and increased apoptotic rates indicating a low stress environment. These findings suggest that strong local cell-cell interactions between primary fibroblastic cells can disrupt the global collective cellular behavior leading to substantial heterogeneity of cell behaviors in constrained monolayers. This local emergent behavior within aggregated fibroblasts may play an important role in development and disease of connective tissues. STATEMENT OF SIGNIFICANCE: Mechanical stress patterns emerging from collective cell behavior play critical roles in morphogenesis, tissue repair, and cancer metastasis. Much has been learned of these collective behaviors by utilizing microcontact printing to constrain cell monolayers (aggregates) into specific shapes. Here we utilize these tools along with long-term video microscopy tracking of individual aggregates to determine how heterogeneous collective behaviors unique to primary fibroblastic cells emerge over time and diverge from computed stress fields. We find that dense multicellular bands form from local collective behavior and disrupt the global collective behavior resulting in heterogeneous patterns of migration, traction stresses, proliferation, and apoptosis. This local emergent behavior within aggregated fibroblasts may play an important role in development and disease of connective tissues.

Dataset Information

Somatic mutations in early metazoan genes disrupt regulatory links between unicellular and multicellular genes in cancer.

Publications

Somatic mutations in early metazoan genes disrupt regulatory links between unicellular and multicellular genes in cancer.

Similar Datasets

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