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Publications

by Keyword: Signal transduction

Hino N, Matsuda K, Jikko Y, Maryu G, Sakai K, Imamura R, Tsukiji S, Aoki K, Terai K, Hirashima T, Trepat X, Matsuda M, (2022). A feedback loop between lamellipodial extension and HGF-ERK signaling specifies leader cells during collective cell migration Developmental Cell 57, 2290-+

Upon the initiation of collective cell migration, the cells at the free edge are specified as leader cells; however, the mechanism underlying the leader cell specification remains elusive. Here, we show that lamellipodial extension after the release from mechanical confinement causes sustained extracellular signal-regulated kinase (ERK) activation and underlies the leader cell specification. Live-imaging of Madin-Darby canine kidney (MDCK) cells and mouse epidermis through the use of Förster resonance energy transfer (FRET)-based biosensors showed that leader cells exhibit sustained ERK activation in a hepatocyte growth factor (HGF)-dependent manner. Meanwhile, follower cells exhibit oscillatory ERK activation waves in an epidermal growth factor (EGF) signaling-dependent manner. Lamellipodial extension at the free edge increases the cellular sensitivity to HGF. The HGF-dependent ERK activation, in turn, promotes lamellipodial extension, thereby forming a positive feedback loop between cell extension and ERK activation and specifying the cells at the free edge as the leader cells. Our findings show that the integration of physical and biochemical cues underlies the leader cell specification during collective cell migration.Copyright © 2022 Elsevier Inc. All rights reserved.

JTD Keywords: activation, c-met, contact inhibition, focal adhesions, heparan-sulfate, mechanical forces, morphogenesis, rho, stress fibers, Collective cell migration, Erk, Feedback regulation, Fret, Growth-factor receptor, Hgf, Lamellipodia, Leader cell specification, Signal transduction, Traction force, Wound healing


Watt, AC, Cejas, P, DeCristo, MJ, Metzger, O, Lam, EYN, Qiu, XT, BrinJones, H, Kesten, N, Coulson, R, Font-Tello, A, Lim, K, Vadhi, R, Daniels, VW, Montero, J, Taing, L, Meyer, CA, Gilan, O, Bell, CC, Korthauer, KD, Giambartolomei, C, Pasaniuc, B, Seo, JH, Freedman, ML, Ma, CT, Ellis, MJ, Krop, I, Winer, E, Letai, A, Brown, M, Dawson, MA, Long, HW, Zhao, JJ, Goel, S, (2021). CDK4/6 inhibition reprograms the breast cancer enhancer landscape by stimulating AP-1 transcriptional activity Nature Cancer 2, 34-+

Goel and colleagues show that CDK4/6 inhibition induces global chromatin changes mediated by AP-1 factors, which mediate key biological and clinical effects in breast cancer. Pharmacologic inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6) were designed to induce cancer cell cycle arrest. Recent studies have suggested that these agents also exert other effects, influencing cancer cell immunogenicity, apoptotic responses and differentiation. Using cell-based and mouse models of breast cancer together with clinical specimens, we show that CDK4/6 inhibitors induce remodeling of cancer cell chromatin characterized by widespread enhancer activation, and that this explains many of these effects. The newly activated enhancers include classical super-enhancers that drive luminal differentiation and apoptotic evasion, as well as a set of enhancers overlying endogenous retroviral elements that are enriched for proximity to interferon-driven genes. Mechanistically, CDK4/6 inhibition increases the level of several activator protein-1 transcription factor proteins, which are in turn implicated in the activity of many of the new enhancers. Our findings offer insights into CDK4/6 pathway biology and should inform the future development of CDK4/6 inhibitors.

JTD Keywords: Abemaciclib, Androgen receptor, Animal experiment, Animal model, Animal tissue, Apoptosis, Article, Breast cancer, C-jun, Cancer cell, Carcinoembryonic antigen related cell adhesion molecule 1, Caspase 3, Cell cycle arrest, Cells, Chromatin, Chromatin immunoprecipitation, Controlled study, Cyclin dependent kinase 4, Cyclin dependent kinase 6, Dna damage, Epidermal growth factor receptor 2, Estrogen receptor, Female, Flow cytometry, Fulvestrant, Hla drb1 antigen, Human, Human cell, Immunoblotting, Immunogenicity, Immunoprecipitation, Interferon, Luciferase assay, Mcf-7 cell line, Mda-mb-231 cell line, Microarray analysis, Morphogenesis, Mouse, Nonhuman, Palbociclib, Protein, Protein expression, Rb, Resistance, Rna polymerase ii, Rna sequence, Selective-inhibition, Senescence, Short tandem repeat, Signal transduction, Tamoxifen, Transcription elongation, Transcription factor, Transcription factor ap 1, Transcriptome, Tumor biopsy, Tumor differentiation, Tumor spheroid, Tumor xenograft, Vinculin, Whole exome sequencing