ArticleCell systems2020
Systems-Level Properties of EGFR-RAS-ERK Signaling Amplify Local Signals to Generate Dynamic Gene Expression Heterogeneity.
Article in Cell systems, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers, 1 of them a synthesis that pooled it.
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Who cites it
37 citing papers in PubMed, 1 synthesis or guideline pooled it, 72 citations in OpenAlex.
- Spatial and temporal intratumoral heterogeneity in breast cancer: a systematic and conceptual review of single-cell and spatial omics studies.BMC cancer · 2026Pooled it
- Macrophage response specificity to ligand mixtures is improved by signaling pathway antagonism.Molecular systems biology · 2026Article
- Amphiregulin drives EGFR-dependent genome stability in colorectal cancer and represents a targetable vulnerability.Oncogene · 2026Article
- PET/CT-based quantification of intratumoral heterogeneity for predicting pathological complete response in breast cancer patients treated with neoadjuvant chemotherapy: A multicentre study.European journal of nuclear medicine and molecular imaging · 2026Article
- Single-cell morphodynamical trajectories enable prediction of gene expression accompanying cell state change.Cell systems · 2026Article
- Are physiological oscillations physiological?The Journal of physiology · 2026Review
- Temozolomide increases the generation of cell heterogeneity in ERK activity in glioma cells.Journal of molecular medicine (Berlin, Germany) · 2026Article
- Exploring gene expression heterogeneity in burn wounds through machine learning models:Annals of medicine and surgery (2012) · 2025Article
- Serial Imaging of Tumour and microEnvironment (SITE) platform for live-cellbioRxiv : the preprint server for biology · 2025Article
- Two novel red-FRET ERK bosensors in the 670-720 nm range.Journal of biological engineering · 2025Article
- A computational workflow for assessing drug effects on temporal signaling dynamics reveals robustness in stimulus-specific NFκB signaling.PLoS computational biology · 2025Article
- Deciphering the history of ERK activity from fixed-cell immunofluorescence measurements.Nature communications · 2025Article
- Exploring the tumor microenvironment of breast cancer to develop a prognostic model and predict immunotherapy responses.Scientific reports · 2025Article
- Multiomics analysis reveals the involvement of NET1 in tumour immune regulation and malignant progression.Scientific reports · 2025Article
- Intratumor heterogeneity of EGFR expression mediates targeted therapy resistance and formation of drug tolerant microenvironment.Nature communications · 2025Article
- USP21-EGFR signaling axis is functionally implicated in metastatic colorectal cancer.Cell death discovery · 2024Article
- Oncogenic EML4-ALK assemblies suppress growth factor perception and modulate drug tolerance.Nature communications · 2024Article
- Mathematical Modeling and Inference of Epidermal Growth Factor-Induced Mitogen-Activated Protein Kinase Cell Signaling Pathways.International journal of molecular sciences · 2024Review
- Featurizing Koopman mode decomposition for robust forecasting.The Journal of chemical physics · 2024Article
- Stimulus-response signaling dynamics characterize macrophage polarization states.Cell systems · 2024Article
Corrections and comments
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Authors and funding
12 authors at 3 institutions in 1 country.
Funding
Abstract
Intratumoral heterogeneity is associated with aggressive tumor behavior, therapy resistance, and poor patient outcomes. Such heterogeneity is thought to be dynamic, shifting over periods of minutes to hours in response to signaling inputs from the tumor microenvironment. However, models of this process have been inferred from indirect or post-hoc measurements of cell state, leaving the temporal details of signaling-driven heterogeneity undefined. Here, we developed a live-cell model system in which microenvironment-driven signaling dynamics can be directly observed and linked to variation in gene expression. Our analysis reveals that paracrine signaling between two cell types is sufficient to drive continual diversification of gene expression programs. This diversification emerges from systems-level properties of the EGFR-RAS-ERK signaling cascade, including intracellular amplification of amphiregulin-mediated paracrine signals and differential kinetic filtering by target genes including Fra-1, c-Myc, and Egr1. Our data enable more precise modeling of paracrine-driven transcriptional variation as a generator of gene expression heterogeneity. A record of this paper's transparent peer review process is included in the Supplemental Information.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.