Tumor cell plasticity, heterogeneity, and resistance in crucial microenvironmental niches in glioma

Erik Jung,Tobias Kessler,Andreas Von Deimling,Wolfgang Wick,Miriam Ratliff,Ruifan Xie,Dirk C Hoffmann,Felix T Kurz,Helin Dogan,Sabine Heiland,Sophie Weil,Matthias Osswald,Frank Winkler,Felix Sahm

doi:10.1038/s41467-021-21117-3

Abstract

Both the perivascular niche (PVN) and the integration into multicellular networks by tumor microtubes (TMs) have been associated with progression and resistance to therapies in glioblastoma, but their specific contribution remained unknown. By long-term tracking of tumor cell fate and dynamics in the live mouse brain, differential therapeutic responses in both niches are determined. Both the PVN, a preferential location of long-term quiescent glioma cells, and network integration facilitate resistance against cytotoxic effects of radiotherapy and chemotherapy—independently of each other, but with additive effects. Perivascular glioblastoma cells are particularly able to actively repair damage to tumor regions. Population of the PVN and resistance in it depend on proficient NOTCH1 expression. In turn, NOTCH1 downregulation induces resistant multicellular networks by TM extension. Our findings identify NOTCH1 as a central switch between the PVN and network niche in glioma, and demonstrate robust cross-compensation when only one niche is targeted.

Highlights

Both the perivascular niche (PVN) and the integration into multicellular networks by tumor microtubes (TMs) have been associated with progression and resistance to therapies in glioblastoma, but their specific contribution remained unknown
Apart from frank angiogenesis, the vasculature of the brain and of the tumor seem to play a special role in glioma biology: a subpopulation of stem-like cells was identified in brain tumors that is potentially responsible for their frequent treatment failure[2,3,4,5], and these stem-like cells can inhabit distinct perivascular niches (PVN)[6,7,8,9,10]
By following patientderived primary glioblastoma cells dynamically for extended periods of time with in vivo two photon microscopy, we here describe mechanisms of tumor progression that depend on interactions with brain microvessels and tumor cell networks, and provide the definitive confirmation that the NOTCH1-dependent PVN is a primary niche of resistance in brain tumors

Summary

Introduction

Both the perivascular niche (PVN) and the integration into multicellular networks by tumor microtubes (TMs) have been associated with progression and resistance to therapies in glioblastoma, but their specific contribution remained unknown. Apart from frank angiogenesis, the vasculature of the brain and of the tumor seem to play a special role in glioma biology: a subpopulation of stem-like cells was identified in brain tumors that is potentially responsible for their frequent treatment failure[2,3,4,5], and these stem-like cells can inhabit distinct perivascular niches (PVN)[6,7,8,9,10] Those stem-like glioma cells share marker expression and molecular traits with neural stem cells (NSCs)[2,3], and NSCs populate distinct neurogenic niches, which include PVN that provide a unique microenvironment for the preservation of the stem cell pool[11]. We demonstrate that NOTCH1 is an important modulator of TMnetwork formation, and interference with this pathway leads to a partial cross-compensation between these two prime niches of resistance in glioma

Methods

Results

Conclusion