Abstract 2168: Longitudinal analysis of diffuse glioma reveals cell state dynamics at recurrence associated with changes in genetics and the microenvironment
Authors: Varn Frederick S. , Johnson Kevin C. , Martinek Jan , Huse Jason T. , Nasrallah MacLean P. , Wesseling Pieter , Cooper Lee A. , Malta Tathiane M. , Wade Taylor E. , Sabedot Thais S. , Brat Daniel J. , Gould Peter V. , Wöehrer Adelheid , Aldape Kenneth , Ismail Azzam , Barthel Floris P. , Kim Hoon , Kocakavuk Emre , Ahmed Nazia , White Kieron , Sivajothi Santhosh , Datta Indrani , Barnholtz-Sloan Jill S. , Bakas Spyridon , D'Angelo Fulvio , Gan Hui K. , Garofano Luciano , Khasraw Mustafa , Migliozzi Simona , Ormond D. Ryan , Paek Sun Ha , Van Meir Erwin G. , Walenkamp Annemiek M. , Watts Colin , Weller Michael , Weiss Tobias , Palucka Karolina , Stead Lucy F. , Poisson Laila M. , Noushmehr Houtan , Iavarone Antonio , Verhaak Roel G. ,   The GLASS Consortium
Published: June 2022

Diffuse glioma is characterized by a poor prognosis and a universal resistance to therapy, though the evolutionary processes behind this resistance remain unclear. The Glioma Longitudinal Analysis (GLASS) Consortium has previously demonstrated that therapy-induced selective pressures shape the genetic evolution of glioma in a stochastic manner. However, single-cell studies have revealed that malignant glioma cells are highly plastic and transition their cell state in response to diverse challenges, including changes in the microenvironment and the administration of standard-of-care therapy. To interrogate the factors driving therapy resistance in diffuse glioma, we collected and analyzed RNA- and/or DNA-sequencing data from temporally separated tumor pairs of over 300 adult patients with IDH-wild-type or IDH-mutant glioma. In a subset of these tumor pairs, we additionally performed multiplex immunofluorescence to capture the spatial relationship between tumor cells and their microenvironment. Recurrent tumors exhibited diverse changes that were attributable to changes in histological features, somatic alterations, and microenvironment interactions. IDH-wild-type tumors overall were more invasive at recurrence and exhibited increased expression of neuronal signaling programs that reflected a possible role for neuronal interactions in promoting glioma progression. In contrast, recurrent IDH-mutant tumors exhibited a significant increase in proliferative expression programs that correlated with discrete genetic changes. Hypermutation and acquired CDKN2A homozygous deletions associated with an increase in proliferating stem-like malignant cells at recurrence in both glioma subtypes, reflecting active tumor expansion. A transition to the mesenchymal phenotype was associated with the presence of a specific myeloid cell state defined by unique ligand-receptor interactions with malignant cells, providing opportunities to target this transition through therapy. Collectively, our results uncover recurrence-associated changes in genetics and the microenvironment that can be targeted to shape disease progression following initial diagnosis.

Citation Format: Frederick S. Varn, Kevin C. Johnson, Jan Martinek, Jason T. Huse, MacLean P. Nasrallah, Pieter Wesseling, Lee A. Cooper, Tathiane M. Malta, Taylor E. Wade, Thais S. Sabedot, Daniel J. Brat, Peter V. Gould, Adelheid Wöehrer, Kenneth Aldape, Azzam Ismail, Floris P. Barthel, Hoon Kim, Emre Kocakavuk, Nazia Ahmed, Kieron White, Santhosh Sivajothi, Indrani Datta, Jill S. Barnholtz-Sloan, Spyridon Bakas, Fulvio D'Angelo, Hui K. Gan, Luciano Garofano, Mustafa Khasraw, Simona Migliozzi, D. Ryan Ormond, Sun Ha Paek, Erwin G. Van Meir, Annemiek M. Walenkamp, Colin Watts, Michael Weller, Tobias Weiss, Karolina Palucka, Lucy F. Stead, Laila M. Poisson, Houtan Noushmehr, Antonio Iavarone, Roel G. Verhaak, The GLASS Consortium. Longitudinal analysis of diffuse glioma reveals cell state dynamics at recurrence associated with changes in genetics and the microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2168.