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.
Highlights
Telomere maintenance is a universal hallmark of cancer
In line with the previous study[13], we verified that loss of ATRX in NHAALT cells (Supplementary Fig. 1c, d) resulted in activation of the alternative lengthening of telomeres (ALT) pathway by confirming the presence of c-circles (Supplementary Fig. 1e), which are extrachromosomal circles of single-stranded telomeric DNA that are considered to be specific and quantifiable markers of the ALT pathway[37,38]
The ALT status of NHAALT cells has previously been confirmed via detection of telomeric sister chromatid exchange (T-SCE), which is another phenotypic hallmark of the ALT pathway[13]
Summary
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. TERT and ALT are hallmarks of tumor proliferation and attractive therapeutic targets, translational methods of imaging TERT and ALT are lacking. Telomerase reverse transcriptase (TERT) expression is the predominant TMM in cancer, including in low-grade oligodendrogliomas (LGOGs)[2,3,4,5]. TERT is the catalytic subunit of the enzyme telomerase that synthesizes telomeric DNA and its expression is silenced at birth in normal somatic cells, with the exception of stem cells[3]. In contrast to LGOGs, low-grade astrocytomas (LGAs) activate a TERT-independent, homologous recombination-mediated mechanism of new telomeric DNA synthesis known as the alternative lengthening of telomeres (ALT) pathway[8,9,10]. Directly targeting TERT activity results in toxicity due to stem cell inhibition[3], inhibiting
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