Therapy-Induced Transdifferentiation Promotes Glioma Growth Independent of EGFR Signaling

Hwanhee Oh, Inah Hwang, Ja Young Jang, Lingxiang Wu, Dongqing Cao, Jun Yao, Haoqiang Ying, Jian Yi Li, Yu Yao, Baoli Hu, Qianghu Wang, Hongwu Zheng, Jihye Paik

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

EGFR is frequently amplified, mutated, and overexpressed in malignant gliomas. Yet the EGFR-targeted therapies have thus far produced only marginal clinical responses, and the underlying mechanism remains poorly understood. Using an inducible oncogenic EGFR-driven glioma mouse model system, our current study reveals that a small population of glioma cells can evade therapyinitiated apoptosis and potentiate relapse development by adopting a mesenchymal-like phenotypic state that no longer depends on oncogenic EGFR signaling. Transcriptome analyses of proximal and distal treatment responses identified TGFb/YAP/Slug signaling cascade activation as a major regulatory mechanism that promotes therapy-induced glioma mesenchymal lineage transdifferentiation. Following anti-EGFR treatment, TGFb secreted from stressed glioma cells acted to promote YAP nuclear translocation that stimulated upregulation of the pro-mesenchymal transcriptional factor SLUG and subsequent glioma lineage transdifferentiation toward a stable therapy-refractory state. Blockade of this adaptive response through suppression of TGFb-mediated YAP activation significantly delayed anti-EGFR relapse and prolonged animal survival. Together, our findings shed new insight into EGFRtargeted therapy resistance and suggest that combinatorial therapies of targeting both EGFR and mechanisms underlying glioma lineage transdifferentiation could ultimately lead to deeper and more durable responses.

Original languageEnglish
Pages (from-to)1528-1539
Number of pages12
JournalCancer Research
Volume81
Issue number6
DOIs
StatePublished - Mar 2021

Bibliographical note

Publisher Copyright:
© 2021 American Association for Cancer Research.

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