Collagen-dependent DDR1 ectodomain shedding regulates proliferative signaling in radiation-resistant glioblastoma
- 1University of Alabama at Birmingham
Abstract
Glioblastoma (GBM) is characterized by near-universal recurrence and resistance to therapy. Although tumor-intrinsic mechanisms of radiation resistance have been extensively studied, how the extracellular matrix influences signaling in radiation-resistant GBM remains poorly understood. Here, we investigated discoidin domain receptor 1 (DDR1), a collagen-activated receptor tyrosine kinase, using matched radiation-sensitive parental and radiation-resistant patient-derived GBM models generated through serial in vivo irradiation. Within a three-dimensional collagen I matrix, radiation-resistant GBM cells exhibited distinct temporal patterns of Ki-67 positivity and ERK1/2 phosphorylation compared with parental cells. Despite increased DDR1 expression, radiation-resistant cells exhibited markedly reduced DDR1 phosphorylation and enhanced ectodomain shedding, characterized by accumulation of the membrane-associated C-terminal fragment and release of the N-terminal fragment. DDR1 depletion reduced ERK1/2 phosphorylation, supporting its contribution to ERK1/2 signaling under these conditions. ADAMTS1 was markedly upregulated in radiation-resistant cells, and its knockdown reduced DDR1 ectodomain shedding while increasing full-length DDR1 abundance, ERK1/2 and RB phosphorylation, cyclin D1 expression, and Ki-67 positivity. Together, these findings reveal a distinct DDR1 regulatory state in acquired radiation-resistant GBM, characterized by enhanced ADAMTS1-associated ectodomain shedding, reduced receptor phosphorylation, and attenuated proliferative signaling within a three-dimensional collagen I matrix.
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BibTeX
@misc{dunlap2026collagendependent,
title = {{Collagen-dependent DDR1 ectodomain shedding regulates proliferative signaling in radiation-resistant glioblastoma}},
author = {S. Dunlap and C. A. Harvey and A. Elkholy and L. Gehrs and M. Mohamed and S. Zakakhosravi and T. L. Schanel and J. M. Murphy and S. T. S. Lim and C. D. Willey and E.-Y. E. Ahn},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.08.757755},
url = {https://www.biorxiv.org/content/10.64898/2026.10.08.757755v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Collagen-dependent DDR1 ectodomain shedding regulates proliferative signaling in radiation-resistant glioblastoma
AU - S. Dunlap
AU - C. A. Harvey
AU - A. Elkholy
AU - L. Gehrs
AU - M. Mohamed
AU - S. Zakakhosravi
AU - T. L. Schanel
AU - J. M. Murphy
AU - S. T. S. Lim
AU - C. D. Willey
AU - E.-Y. E. Ahn
PY - 2026
DA - 2026/10/08
PB - bioRxiv
DO - 10.64898/2026.10.08.757755
UR - https://www.biorxiv.org/content/10.64898/2026.10.08.757755v1
AB - Glioblastoma (GBM) is characterized by near-universal recurrence and resistance to therapy. Although tumor-intrinsic mechanisms of radiation resistance have been extensively studied, how the extracellular matrix influences signaling in radiation-resistant GBM remains poorly understood. Here, we investigated discoidin domain receptor 1 (DDR1), a collagen-activated receptor tyrosine kinase, using matched radiation-sensitive parental and radiation-resistant patient-derived GBM models generated through serial in vivo irradiation. Within a three-dimensional collagen I matrix, radiation-resistant GBM cells exhibited distinct temporal patterns of Ki-67 positivity and ERK1/2 phosphorylation compared with parental cells. Despite increased DDR1 expression, radiation-resistant cells exhibited markedly reduced DDR1 phosphorylation and enhanced ectodomain shedding, characterized by accumulation of the membrane-associated C-terminal fragment and release of the N-terminal fragment. DDR1 depletion reduced ERK1/2 phosphorylation, supporting its contribution to ERK1/2 signaling under these conditions. ADAMTS1 was markedly upregulated in radiation-resistant cells, and its knockdown reduced DDR1 ectodomain shedding while increasing full-length DDR1 abundance, ERK1/2 and RB phosphorylation, cyclin D1 expression, and Ki-67 positivity. Together, these findings reveal a distinct DDR1 regulatory state in acquired radiation-resistant GBM, characterized by enhanced ADAMTS1-associated ectodomain shedding, reduced receptor phosphorylation, and attenuated proliferative signaling within a three-dimensional collagen I matrix.
ER -