Therapy-Induced Transdifferentiation Promotes Glioma Growth Independent of EGFR Signaling.

TitleTherapy-Induced Transdifferentiation Promotes Glioma Growth Independent of EGFR Signaling.
Publication TypeJournal Article
Year of Publication2021
AuthorsOh H, Hwang I, Jang J-Y, Wu L, Cao D, Yao J, Ying H, Li JYi, Yao Y, Hu B, Wang Q, Zheng H, Paik J
JournalCancer Res
Date Published2021 03 15
KeywordsAdaptor Proteins, Signal Transducing, Animals, Antineoplastic Combined Chemotherapy Protocols, Apoptosis, Brain Neoplasms, Cell Line, Tumor, Cell Proliferation, Cell Transdifferentiation, Datasets as Topic, Disease Models, Animal, Drug Resistance, Neoplasm, ErbB Receptors, Erlotinib Hydrochloride, Female, Gene Expression Regulation, Neoplastic, Glioma, Homeodomain Proteins, Humans, Male, Mice, Mice, Knockout, Neoplasm Recurrence, Local, Prognosis, Progression-Free Survival, RNA-Seq, Signal Transduction, Transcription Factors, Transforming Growth Factor beta1, Xenograft Model Antitumor Assays

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.

Alternate JournalCancer Res
PubMed ID33509942
Related Faculty: 
Hongwu Zheng, Ph.D. Ji-Hye Paik, Ph.D.

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