Optogenetic control of NOTCH1 signaling

Joanna Kałafut, Jakub Czapiński, Alicja Przybyszewska-Podstawka, Arkadiusz Czerwonka, Adrian Odrzywolski, Cecilia Sahlgren, Adolfo Rivero-Müller

Research output: Contribution to journalArticleScientificpeer-review

7 Citations (Scopus)
87 Downloads (Pure)

Abstract

The Notch signaling pathway is a crucial regulator of cell differentiation as well as tissue organization, whose deregulation is linked to the pathogenesis of different diseases. NOTCH1 plays a key role in breast cancer progression by increasing proliferation, maintenance of cancer stem cells, and impairment of cell death. NOTCH1 is a mechanosensitive receptor, where mechanical force is required to activate the proteolytic cleavage and release of the Notch intracellular domain (NICD). We circumvent this limitation by regulating Notch activity by light. To achieve this, we have engineered an optogenetic NOTCH1 receptor (optoNotch) to control the activation of NOTCH1 intracellular domain (N1ICD) and its downstream transcriptional activities. Using optoNotch we confirm that NOTCH1 activation increases cell proliferation in MCF7 and MDA-MB-468 breast cancer cells in 2D and spheroid 3D cultures, although causing distinct cell-type specific migratory phenotypes. Additionally, optoNotch activation induced chemoresistance on the same cell lines. OptoNotch allows the fine-tuning, ligand-independent, regulation of N1ICD activity and thus a better understanding of the spatiotemporal complexity of Notch signaling. [MediaObject not available: see fulltext.]

Original languageEnglish
Article number67
Pages (from-to)67
JournalCell Communication and Signaling
Volume20
Issue number1
DOIs
Publication statusPublished - Dec 2022
MoE publication typeA1 Journal article-refereed

Keywords

  • Notch signaling
  • Notch1
  • Light-activation
  • Breast cancer
  • Optogenetics

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