Systemic brain dissemination of glioblastoma requires transdifferentiation into endothelial-like cells via TGF-β-ALK1-Smad1/5 signaling.

in Neoplasia (New York, N.Y.) by Thomas M B Ware, Adilson Fonseca Teixeira, Josephine Iaria, Rodney B Luwor, Hong-Jian Zhu

TLDR

  • A study reveals that glioblastoma tumour cells can transform into endothelial-like cells, leading to the dissemination of tumour cells throughout the brain
  • Targeting the TGF-β-ALK1-Smad1/5 pathway can impair this process and slow glioblastoma progression

Abstract

Glioblastoma is the most aggressive type of brain cancer, but treatment improvements for glioblastoma patients remain stagnated for over 20 years. This is despite the large number of clinical trials that have attempted to replicate the success of therapeutics developed for other cancer types. This discrepancy highlights the urgent need to decipher the unique biology of glioblastomas. Here, we show that glioblastoma tumour cells are highly plastic, integrating into blood vessel walls to disseminate throughout the brain. This relies on the transdifferentiation of glioblastoma tumor cells into endothelial-like cells in a process we termed endothelialisation. Mechanistically, in addition to TGF-β-ALK5-Smad2/3 signaling, glioblastoma tumour cells also activate TGF-β-ALK1-Smad1/5 signaling - a mechanism previously thought to be limited to endothelial cells. Consequently, therapeutic targeting of TGF-β-ALK1-Smad1/5 activity impaired endothelialisation-driven glioblastoma progression. This study identifies a previously unknown component of glioblastoma biology and establishes a therapeutic approach to reduce the progression of this disease.

Overview

  • bbox the study is focused on deciphering the unique biology of glioblastoma
  • bullet The study employed an experimental approach to investigate the tumour cells' behavior and their interactions with blood vessels
  • bullet The study aimed to identify a previously unknown component of glioblastoma biology and explore a potential therapeutic approach to its treatment

Comparative Analysis & Findings

  • bullet The study found that glioblastoma tumour cells are highly plastic and can integrate into blood vessel walls to disseminate throughout the brain
  • bullet The process by which this occurs is called endothelialisation, which relies on the transdifferentiation of glioblastoma tumor cells into endothelial-like cells
  • bullet Therapeutic targeting of TGF-β-ALK1-Smad1/5 activity impaired endothelialisation-driven glioblastoma progression

Implications and Future Directions

  • bullet The study's findings highlight the urgent need to understand the unique biology of glioblastoma to improve treatment outcomes
  • bullet Future studies could explore additional therapeutic approaches targeting TGF-β-ALK1-Smad1/5 signaling and endothelialisation
  • bullet Elucidating the molecular mechanisms underlying glioblastoma biology will likely require collaboration between researchers from various disciplines
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