Characterization of simaphagy as cellular signaling surveillance process and its potential role in carcinogenesis

• Applicant: Dr. Ann-Christin Borchers
• Subject Area: Cell Biology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 558582335

Cells constantly communicate with their environment and integrate various signal inputs. Receptor-mediated signaling in cells is a spatiotemporally tightly regulated process. External signal cues arriving at the plasma membrane are transduced into the cell by a variety of membrane-residual receptors. Ligand-bound receptors get endocytosed and segregated into endosomal sub compartments in an ESCRT machinery dependent manner. This sorting eventually leads to signal termination. Defects in the ESCRT machinery result in prolonged receptor activation on endosomes which is associated with various types of cancer. Recently, a process termed simaphagy was identified as a novel failsafe mechanism to remove these hyper-signaling endosomes. Upon simaphagy induction, components of the autophagy machinery get recruited and endosomes are encapsulated by autophagic structures for subsequent lysosomal degradation and signal termination. In the absence of the ESCRT-I subunit VPS37 this process is perturbed, resulting in sustained cellular signaling from endosomes and increased cell migration. However, the mechanisms of the spatiotemporal regulation of simaphagy and the consequences of impaired simaphagy on cellular signaling as well as the potential role in carcinogenesis have not been investigated so far. The proposed project aims to provide details on these open research questions. To do so, immunofluorescence- and life-cell microscopy will be combined with molecular biology techniques, migration and invasion assays, mass spectrometry-based secretome and signaling pathway analysis. The expected outcome of this project will lead to a more detailed understanding of simaphagy, the cellular program that promotes hyper-signalling endosome clearance. This project will further provide insights into the consequences of stalled simaphagy on the onset of VPS37-associated diseases and carcinogenesis. These insights have the long-term potential to identify new therapeutic targets to counteract the effects of prolonged receptor signaling and to provide improved treatment options for cancers with reduced VPS37 expression.

• DFG Programme: WBP Fellowship
• International Connection: Norway
• Host: Professor Dr. Harald Alfred Stenmark