LNX1 modulates Notch1 signaling to promote expansion of the glioma stem cell population during temozolomide therapy in glioblastoma

Shivani Baisiwala, Robert R. Hall, Miranda R. Saathoff, Jack M. Shireman, Cheol Park, Shreya Budhiraja, Chirag Goel, Louisa Warnke, Clare Hardiman, Jennifer Y. Wang, Katy McCortney, Craig M. Horbinski, Atique U. Ahmed*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Glioblastoma (GBM) is the most common primary brain malignancy in adults, with a 100% recurrence rate and 21-month median survival. Our lab and others have shown that GBM contains a subpopulation of glioma stem cells (GSCs) that expand during chemotherapy and may contribute to therapeutic resistance and recurrence in GBM. To investigate the mechanism behind this expansion, we applied gene set expression analysis (GSEA) to patient-derived xenograft (PDX) cells in response to temozolomide (TMZ), the most commonly used chemotherapy against GBM. Results showed significant enrichment of cancer stem cell and cell cycle pathways (False Discovery Rate (FDR) < 0.25). The ligand of numb protein 1 (LNX1), a known regulator of Notch signaling by targeting negative regulator Numb, is strongly upregulated after TMZ therapy (p < 0.0001) and is negatively correlated with survival of GBM patients. LNX1 is also upregulated after TMZ therapy in multiple PDX lines with concomitant downregulations in Numb and upregulations in intracellular Notch1 (NICD). Overexpression of LNX1 results in Notch1 signaling activation and increased GSC populations. In contrast, knocking down LNX1 reverses these changes, causing a significant downregulation of NICD, reduction in stemness after TMZ therapy, and resulting in more prolonged median survival in a mouse model. Based on this, we propose that during anti-GBM chemotherapy, LNX1-regulated Notch1 signaling promotes stemness and contributes to therapeutic resistance.

Original languageEnglish (US)
Article number3505
Pages (from-to)1-19
Number of pages19
JournalCancers
Volume12
Issue number12
DOIs
StatePublished - Dec 2020

Keywords

  • Glioblastoma
  • Glioma stem cell
  • LNX1
  • Notch1
  • Therapeutic resistance

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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