2. Academic Validation
  3. Invasive growth of brain metastases is linked to CHI3L1 release from pSTAT3-positive astrocytes

Invasive growth of brain metastases is linked to CHI3L1 release from pSTAT3-positive astrocytes

  • Neuro Oncol. 2024 Jan 25:noae013. doi: 10.1093/neuonc/noae013.
Matthew Dankner 1 2,  Sarah M Maritan 1 2,  Neibla Priego 3,  Georgia Kruck 1,  Andriniaina Nkili-Meyong 4 5,  Javad Nadaf 4 5,  Rebecca Zhuang 6,  Matthew G Annis 1,  Dongmei Zuo 1,  Alexander Nowakowski 1 2,  Marco Biondini 1,  Alexander Kiepas 7,  Caitlyn Mourcos 1 2,  Phuong Le 4 5,  Francois Charron 8,  Yanis Inglebert 9,  Paul Savage 10,  Louis Théret 11,  Marie-Christine Guiot 1 4 5 12,  R Anne McKinney 8,  William J Muller 1 13,  Morag Park 1 2 12 13,  Manuel Valiente 3,  Kevin Petrecca 4 5,  Peter M Siegel 1 2 13
Affiliations

Affiliations

  • 1 Rosalind and Morris Goodman Cancer Institute, McGill University, Montreal, QC, Canada.
  • 2 Department of Medicine, Division of Experimental Medicine, McGill University, Montreal, QC, Canada.
  • 3 Brain Metastasis Group, Spanish National Cancer Research Center (CNIO), Madrid, Spain.
  • 4 Department of Neurology and Neurosurgery, Faculty of Medicine, McGill University, Montreal, QC, Canada.
  • 5 Montreal Neurological Institute-Hospital, McGill University Health Centre, Montreal, QC, Canada.
  • 6 Department of Medicine, University of British Columbia, Vancouver, BC, Canada.
  • 7 Cell Biology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA.
  • 8 Department of Pharmacology, McGill University, Montreal, QC, Canada.
  • 9 Department of Neurosciences, University of Montreal, Montreal, QC, Canada.
  • 10 Department of Surgery, University of Toronto, Toronto, ON, Canada.
  • 11 Research Institute of the University of Montreal (IRIC), Montreal, QC, Canada.
  • 12 Department of Pathology, Faculty of Medicine, McGill University, Montreal, QC, Canada.
  • 13 Department of Biochemistry, Faculty of Medicine, McGill University, Montreal, QC, Canada.
PMID: 38271182 DOI: 10.1093/neuonc/noae013
Abstract

Background: Compared to minimally invasive brain metastases (MI BrM), highly invasive (HI) lesions form abundant contacts with cells in the peritumoral brain parenchyma and are associated with poor prognosis. Reactive astrocytes (Ras) labeled by phosphorylated STAT3 (pSTAT3) have recently emerged as a promising therapeutic target for BrM. Here, we explore whether BrM invasion pattern is influenced by pSTAT3+ Ras and may serve as a predictive biomarker for STAT3 inhibition.

Methods: We used immunohistochemistry to identify pSTAT3+ Ras in HI and MI human and patient-derived xenograft (PDX) BrM. Using PDX, syngeneic, and transgenic mouse models of HI and MI BrM, we assessed how pharmacological STAT3 inhibition or RA-specific STAT3 genetic ablation affected BrM growth in vivo. Cancer cell invasion was modeled in vitro using a brain slice-tumor co-culture assay. We performed single-cell RNA sequencing of human BrM and adjacent brain tissue.

Results: Ras expressing pSTAT3 are situated at the brain-tumor interface and drive BrM invasive growth. HI BrM invasion pattern was associated with delayed growth in the context of STAT3 inhibition or genetic ablation. We demonstrate that pSTAT3+ Ras secrete Chitinase 3-like-1 (CHI3L1), which is a known STAT3 transcriptional target. Furthermore, single-cell RNA sequencing identified CHI3L1-expressing Ras in human HI BrM. STAT3 activation, or recombinant CHI3L1 alone, induced Cancer cell invasion into the brain parenchyma using a brain slice-tumor plug co-culture assay.

Conclusions: Together, these data reveal that pSTAT3+ RA-derived CHI3L1 is associated with BrM invasion, implicating STAT3 and CHI3L1 as clinically relevant therapeutic targets for the treatment of HI BrM.

Keywords

CHI3L1; STAT3; astrocyte; brain metastasis; histopathological growth patterns; invasion.

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