ADAMDEC1 Maintains a Growth Factor Signaling Loop in Cancer Stem Cells.

in Cancer discovery by Ana Jimenez-Pascual, James S Hale, Anja Kordowski, Jamie Pugh, Daniel J Silver, Defne Bayik, Gustavo Roversi, Tyler J Alban, Shilpa Rao, Rui Chen, Thomas M McIntyre, Giorgio Colombo, Giulia Taraboletti, Karl O Holmberg, Karin Forsberg-Nilsson, Justin D Lathia, Florian A Siebzehnrubl

TLDR

  • The study identified a novel signaling axis involving ADAMDEC1 that maintains Glioblastoma cancer stem cells and found that targeting this axis may be a new therapeutic strategy for GBM treatment.
  • Key Insights: The study reveals a new mechanism of GSC maintenance and highlights the potential therapeutic target.
  • The research provides a new avenue for investigating GBM and potentially developing more effective treatments for this devastating disease.

Abstract

Glioblastomas (GBM) are lethal brain tumors where poor outcome is attributed to cellular heterogeneity, therapeutic resistance, and a highly infiltrative nature. These characteristics are preferentially linked to GBM cancer stem cells (GSC), but how GSCs maintain their stemness is incompletely understood and the subject of intense investigation. Here, we identify a novel signaling loop that induces and maintains GSCs consisting of an atypical metalloproteinase, ADAMDEC1, secreted by GSCs. ADAMDEC1 rapidly solubilizes FGF2 to stimulate FGFR1 expressed on GSCs. FGFR1 signaling induces upregulation of ZEB1 via ERK1/2 that regulates ADAMDEC1 expression through miR-203, creating a positive feedback loop. Genetic or pharmacologic targeting of components of this axis attenuates self-renewal and tumor growth. These findings reveal a new signaling axis for GSC maintenance and highlight ADAMDEC1 and FGFR1 as potential therapeutic targets in GBM. SIGNIFICANCE: Cancer stem cells (CSC) drive tumor growth in many cancers including GBM. We identified a novel sheddase, ADAMDEC1, which initiates an FGF autocrine loop to promote stemness in CSCs. This loop can be targeted to reduce GBM growth..

Overview

  • briefly describe the main focus of the study and the hypothesis being tested.
  • The study aimed to identify a novel signaling loop that induces and maintains Glioblastoma cancer stem cells (GSCs).
  • The hypothesis tested was the role of ADAMDEC1 in GSC maintenance and the potential for targeting it as a therapeutic strategy.

Comparative Analysis & Findings

  • Compare the outcomes observed under different experimental conditions or interventions detailed in the study.
  • The study found that targeting ADAMDEC1 and FGFR1 components of the axis attenuates self-renewal and tumor growth.
  • The FGF autocrine loop, initiated by ADAMDEC1, promotes stemness in CSCs, providing a potential therapeutic target for GBM treatment.

Implications and Future Directions

  • Explain the significance of the study's findings and their potential impact on the field of research or clinical practice.
  • The study highlights the potential for targeting ADAMDEC1 and FGFR1 as therapeutic strategies for treating GBM.
  • Future research should investigate the molecular mechanisms underlying this signaling axis and its role in other types of cancer.
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