1. Academic Validation
  2. Loss of PTPRS elicits potent metastatic capability and resistance to temozolomide in glioblastoma

Loss of PTPRS elicits potent metastatic capability and resistance to temozolomide in glioblastoma

  • Mol Carcinog. 2024 Mar 22. doi: 10.1002/mc.23720.
Yihua Zhang 1 Liugang Chang 1 Ping Huang 1 Min Cao 1 Rujun Hong 1 Xinhu Zhao 1 Xuzhi He 1 Lunshan Xu 1
Affiliations

Affiliation

  • 1 Department of Neurosurgery, Daping Hospital, The Army Medical University, Chongqing, China.
Abstract

Glioblastoma (GBM) is the most aggressive brain tumor type with worse clinical outcome due to the hallmarks of strong invasiveness, high rate of recurrence, and therapeutic resistance to temozolomide (TMZ), the first-line drug for GBM, representing a major challenge for successful GBM therapeutics. Understanding the underlying mechanisms that drive GBM progression will shed novel insight into therapeutic strategies. Receptor-type tyrosine-protein Phosphatase S (PTPRS) is a frequently mutated gene in human cancers, including GBM. Its role in GBM has not yet been clarified. Here, inactivating PTPRS mutation or deficiency was frequently found in GBM, and deficiency in PTPRS significantly induced defects in the G2M checkpoint and limited GBM cells proliferation, leading to potent resistance to TMZ treatment in vitro and in vivo. Surprisingly, loss of PTPRS triggered an unexpected mesenchymal phenotype that markedly enhances the migratory capabilities of GBM cells through upregulating numerous Matrix Metalloproteinases via MAPK-MEK-ERK signaling. Therefore, this work provides a therapeutic window for precisely excluding PTPRS-mutated patients who do not respond to TMZ.

Keywords

PTPRS; chemoresistance; glioblastoma; metastasis; temozolomide.

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