1. Therapy-Induced Transdifferentiation Promotes Glioma Growth Independent of EGFR Signaling
- Author
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Jun Yao, Inah Hwang, Hongwu Zheng, J. Li, Qianghu Wang, Lingxiang Wu, Baoli Hu, Dongqing Cao, Ja Young Jang, Haoqiang Ying, Yu Yao, Hwanhee Oh, and Jihye Paik
- Subjects
Male ,0301 basic medicine ,Cancer Research ,Datasets as Topic ,Apoptosis ,Transcriptome ,Mice ,0302 clinical medicine ,Antineoplastic Combined Chemotherapy Protocols ,RNA-Seq ,Epidermal growth factor receptor ,Mice, Knockout ,education.field_of_study ,biology ,Brain Neoplasms ,Transdifferentiation ,Glioma ,Prognosis ,Progression-Free Survival ,ErbB Receptors ,Gene Expression Regulation, Neoplastic ,Oncology ,030220 oncology & carcinogenesis ,Female ,Signal Transduction ,Slug ,Population ,Transforming Growth Factor beta1 ,Erlotinib Hydrochloride ,03 medical and health sciences ,Downregulation and upregulation ,Cell Line, Tumor ,medicine ,Animals ,Humans ,education ,Adaptor Proteins, Signal Transducing ,Cell Proliferation ,Homeodomain Proteins ,Mesenchymal stem cell ,YAP-Signaling Proteins ,medicine.disease ,biology.organism_classification ,Xenograft Model Antitumor Assays ,Disease Models, Animal ,030104 developmental biology ,Drug Resistance, Neoplasm ,Cell Transdifferentiation ,Cancer research ,biology.protein ,Neoplasm Recurrence, Local ,Transcription Factors - 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 therapy-initiated 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 TGFβ/YAP/Slug signaling cascade activation as a major regulatory mechanism that promotes therapy-induced glioma mesenchymal lineage transdifferentiation. Following anti-EGFR treatment, TGFβ 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 TGFβ-mediated YAP activation significantly delayed anti-EGFR relapse and prolonged animal survival. Together, our findings shed new insight into EGFR-targeted 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. Significance: This study demonstrates that molecular reprogramming and lineage transdifferentiation underlie anti-EGFR therapy resistance and are clinically relevant to the development of new combinatorial targeting strategies against malignant gliomas with aberrant EGFR signaling.
- Published
- 2021