Multi-range ERK responses shape the proliferative trajectory of single cells following oncogene induction
Jia-Yun Chen,
Clemens Hug,
José Reyes,
Chengzhe Tian,
Luca Gerosa,
Fabian Fröhlich,
Bas Ponsioen,
Hugo J.G. Snippert,
Sabrina L. Spencer,
Ashwini Jambhekar,
Peter K. Sorger,
Galit Lahav
Affiliations
Jia-Yun Chen
Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA
Clemens Hug
Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA 02115, USA
José Reyes
Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA; Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
Chengzhe Tian
Department of Biochemistry, University of Colorado Boulder, Boulder, CO 80303, USA; BioFrontiers Institute, University of Colorado Boulder, Boulder, CO 80303, USA; Research Center for Molecular Medicine, Austrian Academy of Sciences, Vienna, Austria
Luca Gerosa
Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA; Genentech, Inc, South San Francisco, CA 94080, USA
Fabian Fröhlich
Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA
Bas Ponsioen
Molecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands; Oncode Institute, Utrecht, the Netherlands
Hugo J.G. Snippert
Molecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands; Oncode Institute, Utrecht, the Netherlands
Sabrina L. Spencer
Department of Biochemistry, University of Colorado Boulder, Boulder, CO 80303, USA; BioFrontiers Institute, University of Colorado Boulder, Boulder, CO 80303, USA
Ashwini Jambhekar
Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA; Ludwig Center at Harvard Medical School, Boston, MA, USA
Peter K. Sorger
Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA; Ludwig Center at Harvard Medical School, Boston, MA, USA; Corresponding author
Galit Lahav
Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA; Ludwig Center at Harvard Medical School, Boston, MA, USA; Corresponding author
Summary: Oncogene-induced senescence is a phenomenon in which aberrant oncogene expression causes non-transformed cells to enter a non-proliferative state. Cells undergoing oncogenic induction display phenotypic heterogeneity, with some cells senescing and others remaining proliferative. The causes of heterogeneity remain unclear. We studied the sources of heterogeneity in the responses of human epithelial cells to oncogenic BRAFV600E expression. We found that a narrow expression range of BRAFV600E generated a wide range of activities of its downstream effector ERK. In population-level and single-cell assays, ERK activity displayed a non-monotonic relationship to proliferation, with intermediate ERK activities leading to maximal proliferation. We profiled gene expression across a range of ERK activities over time and characterized four distinct ERK response classes, which we propose act in concert to generate the ERK-proliferation response. Altogether, our studies map the input-output relationships between ERK activity and proliferation, elucidating how heterogeneity can be generated during oncogene induction.
