Characterization of the minimal residual disease state reveals distinct evolutionary trajectories of human glioblastoma

Maleeha A. Qazi, Sabra K. Salim, Kevin R. Brown, Nicholas Mikolajewicz, Neil Savage, Hong Han, Minomi K. Subapanditha, David Bakhshinyan, Allison Nixon, Parvez Vora, Kimberly Desmond, Chirayu Chokshi, Mohini Singh, Amanda Khoo, Andrew Macklin, Shahbaz Khan, Nazanin Tatari, Neil Winegarden, Laura Richards, Trevor PughNicholas Bock, Alireza Mansouri, Chitra Venugopal, Thomas Kislinger, Sidhartha Goyal, Jason Moffat, Sheila K. Singh

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Recurrence of solid tumors renders patients vulnerable to advanced, treatment-refractory disease state with mutational and oncogenic landscape distinctive from initial diagnosis. Improving outcomes for recurrent cancers requires a better understanding of cell populations that expand from the post-therapy, minimal residual disease (MRD) state. We profile barcoded tumor stem cell populations through therapy at tumor initiation, MRD, and recurrence in our therapy-adapted, patient-derived xenograft models of glioblastoma (GBM). Tumors show distinct patterns of recurrence in which clonal populations exhibit either a pre-existing fitness advantage or an equipotency fitness acquired through therapy. Characterization of the MRD state by single-cell and bulk RNA sequencing reveals a tumor-intrinsic immunomodulatory signature with prognostic significance at the transcriptomic level and in proteomic analysis of cerebrospinal fluid (CSF) collected from patients with GBM. Our results provide insight into the innate and therapy-driven dynamics of human GBM and the prognostic value of interrogating the MRD state in solid cancers.

Original languageEnglish (US)
Article number111420
JournalCell Reports
Volume40
Issue number13
DOIs
StatePublished - Sep 27 2022

All Science Journal Classification (ASJC) codes

  • General Biochemistry, Genetics and Molecular Biology

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