Tumor edge-to-core transition promotes malignancy in primary-to-recurrent glioblastoma progression in a PLAGL1/CD109-mediated mechanism

Chaoxi Li; Hee Jin Cho; Daisuke Yamashita; Moaaz Abdelrashid; Qin Chen; Soniya Bastola; Gustavo Chagoya; Galal A Elsayed; Svetlana Komarova; Saya Ozaki; Yoshihiro Ohtsuka; Takeharu Kunieda; Harley I Kornblum; Toru Kondo; Do-Hyun Nam; Ichiro Nakano

doi:10.1093/noajnl/vdaa163

Tumor edge-to-core transition promotes malignancy in primary-to-recurrent glioblastoma progression in a PLAGL1/CD109-mediated mechanism

Neurooncol Adv. 2020 Nov 27;2(1):vdaa163. doi: 10.1093/noajnl/vdaa163. eCollection 2020 Jan-Dec.

Authors

Chaoxi Li¹, Hee Jin Cho^{2

3}, Daisuke Yamashita⁴, Moaaz Abdelrashid⁵, Qin Chen⁶, Soniya Bastola⁷, Gustavo Chagoya⁸, Galal A Elsayed⁸, Svetlana Komarova⁸, Saya Ozaki⁴, Yoshihiro Ohtsuka⁴, Takeharu Kunieda⁴, Harley I Kornblum⁷, Toru Kondo⁹, Do-Hyun Nam^{2

3

10}, Ichiro Nakano^{4

11}

Affiliations

¹ Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
² Research Institute for Future Medicine, Samsung Medical Center, Seoul, Republic of Korea.
³ Institute for Refractory Cancer Research, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
⁴ Department of Neurosurgery, Ehime University, Japan.
⁵ Department of Neurology, University of Alabama at Birmingham, Birmingham, Alabama, USA.
⁶ Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
⁷ Intellectual and Developmental Disabilities Research Center, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
⁸ Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, Alabama, USA.
⁹ Division of Stem Cell Biology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan.
¹⁰ Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
¹¹ Research and Development Center for Precision Medicine, Tsukuba University, Tsukuba, Japan.

Abstract

Background: Glioblastoma remains highly lethal due to its inevitable recurrence. Most of this recurrence is found locally, indicating that postsurgical tumor-initiating cells (TICs) accumulate at the tumor edge. These edge-TICs then generate local recurrence harboring new core lesions. Here, we investigated the clinical significance of the edge-to-core (E-to-C) signature generating glioblastoma recurrence and sought to identify its central mediators.

Methods: First, we examined the association of E-to-C-related expression changes to patient outcome in matched primary and recurrent samples (n = 37). Specifically, we tested whether the combined decrease of the edge-TIC marker PROM1 (CD133) with the increase of the core-TIC marker CD109, representing E-to-C transition during the primary-to-recurrence progression, indicates poorer patient outcome. We then investigated the specific molecular mediators that trigger tumor recurrence driven by the E-to-C progression. Subsequently, the functional and translational significance of the identified molecule was validated with our patient-derived edge-TIC models in vitro and in vivo.

Results: Patients exhibiting the CD133^low/CD109^high signature upon recurrence representing E-to-C transition displayed a strong association with poorer progression-free survival and overall survival among all tested patients. Differential gene expression identified that PLAGL1 was tightly correlated with the core TIC marker CD109 and was linked to shorter patient survival. Experimentally, forced PLAGL1 overexpression enhanced, while its knockdown reduced, glioblastoma edge-derived tumor growth in vivo and subsequent mouse survival, suggesting its essential role in the E-to-C-mediated glioblastoma progression.

Conclusions: E-to-C axis represents an ongoing lethal process in primary glioblastoma contributing to its recurrence, partly in a PLAGL1/CD109-mediated mechanism.

Keywords: cancer stem cell; glioma stem cell; recurrence-initiating cell; spatial identity.

Abstract

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