Non-invasive assessment of telomere maintenance mechanisms in brain tumors

Pavithra Viswanath (), Georgios Batsios, Joydeep Mukherjee, Anne Marie Gillespie, Peder E. Z. Larson, H. Artee Luchman, Joanna J. Phillips, Joseph F. Costello, Russell O. Pieper and Sabrina M. Ronen ()
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Pavithra Viswanath: University of California San Francisco
Georgios Batsios: University of California San Francisco
Joydeep Mukherjee: University of California San Francisco
Anne Marie Gillespie: University of California San Francisco
Peder E. Z. Larson: University of California San Francisco
H. Artee Luchman: University of Calgary
Joanna J. Phillips: University of California San Francisco
Joseph F. Costello: University of California San Francisco
Russell O. Pieper: University of California San Francisco
Sabrina M. Ronen: University of California San Francisco

Nature Communications, 2021, vol. 12, issue 1, 1-18

Abstract: Abstract Telomere maintenance is a universal hallmark of cancer. Most tumors including low-grade oligodendrogliomas use telomerase reverse transcriptase (TERT) expression for telomere maintenance while astrocytomas use the alternative lengthening of telomeres (ALT) pathway. Although TERT and ALT are hallmarks of tumor proliferation and attractive therapeutic targets, translational methods of imaging TERT and ALT are lacking. Here we show that TERT and ALT are associated with unique 1H-magnetic resonance spectroscopy (MRS)-detectable metabolic signatures in genetically-engineered and patient-derived glioma models and patient biopsies. Importantly, we have leveraged this information to mechanistically validate hyperpolarized [1-13C]-alanine flux to pyruvate as an imaging biomarker of ALT status and hyperpolarized [1-13C]-alanine flux to lactate as an imaging biomarker of TERT status in low-grade gliomas. Collectively, we have identified metabolic biomarkers of TERT and ALT status that provide a way of integrating critical oncogenic information into non-invasive imaging modalities that can improve tumor diagnosis and treatment response monitoring.

Date: 2021
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DOI: 10.1038/s41467-020-20312-y

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