Microenvironmental signals and biochemical information processing

Cooperative determinants of intratumoral plasticity and heterogeneity

Alexander E. Davies, John Albeck

Research output: Contribution to journalReview article

4 Citations (Scopus)

Abstract

Intra-tumor cellular heterogeneity is a major challenge in cancer therapy. Tumors are composed of multiple phenotypic subpopulations that vary in their ability to initiate metastatic tumors and in their sensitivity to chemotherapy. In many cases, cells can transition between these subpopulations, not by genetic mutation, but instead through reversible changes in signal transduction or gene expression programs. This plasticity begins at the level of the microenvironment where local autocrine and paracrine signals, exosomes, tumor-stroma interactions, and extracellular matrix (ECM) composition create a signaling landscape that varies over space and time. The integration of this complex array of signals engages signaling pathways that control gene expression. The resulting modulation of gene expression programs causes individual cells to sample a wide array of phenotypic states that support tumor growth, dissemination, and therapeutic resistance. In this review, we discuss how information flows dynamically within the microenvironmental landscape to inform cell state decisions and to create intra-tumoral heterogeneity. We address the role of plasticity in the acquisition of transient and prolonged drug resistant states and discuss how targeted pharmacological modification of the signaling landscape may be able to constrain phenotypic plasticity, leading to improved treatment responses.

Original languageEnglish (US)
Article number44
JournalFrontiers in Cell and Developmental Biology
Volume6
Issue numberAPR
DOIs
StatePublished - Apr 20 2018

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Automatic Data Processing
Neoplasms
Gene Expression
Exosomes
Extracellular Matrix
Signal Transduction
Therapeutics
Pharmacology
Drug Therapy
Mutation
Growth
Pharmaceutical Preparations

Keywords

  • Epithelial-to-mesenchymal transition
  • Kinase
  • Neoplastic
  • Network state transition
  • Receptor
  • Single-cell
  • Stem cell

ASJC Scopus subject areas

  • Developmental Biology
  • Cell Biology

Cite this

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abstract = "Intra-tumor cellular heterogeneity is a major challenge in cancer therapy. Tumors are composed of multiple phenotypic subpopulations that vary in their ability to initiate metastatic tumors and in their sensitivity to chemotherapy. In many cases, cells can transition between these subpopulations, not by genetic mutation, but instead through reversible changes in signal transduction or gene expression programs. This plasticity begins at the level of the microenvironment where local autocrine and paracrine signals, exosomes, tumor-stroma interactions, and extracellular matrix (ECM) composition create a signaling landscape that varies over space and time. The integration of this complex array of signals engages signaling pathways that control gene expression. The resulting modulation of gene expression programs causes individual cells to sample a wide array of phenotypic states that support tumor growth, dissemination, and therapeutic resistance. In this review, we discuss how information flows dynamically within the microenvironmental landscape to inform cell state decisions and to create intra-tumoral heterogeneity. We address the role of plasticity in the acquisition of transient and prolonged drug resistant states and discuss how targeted pharmacological modification of the signaling landscape may be able to constrain phenotypic plasticity, leading to improved treatment responses.",
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