Abstract
Although metastasis is the most common cause of cancer deaths, metastasis-intrinsic dependencies remain largely uncharacterized. We previously reported that metastatic pancreatic cancers were dependent on the glucose-metabolizing enzyme phosphogluconate dehydrogenase (PGD). Surprisingly, PGD catalysis was constitutively elevated without activating mutations, suggesting a non-genetic basis for enhanced activity. Here we report a metabolic adaptation that stably activates PGD to reprogram metastatic chromatin. High PGD catalysis prevents transcriptional up-regulation of thioredoxin-interacting protein (TXNIP), a gene that negatively regulates glucose import. This allows glucose consumption rates to rise in support of PGD, while simultaneously facilitating epigenetic reprogramming through a glucose-fueled histone hyperacetylation pathway. Restoring TXNIP normalizes glucose consumption, lowers PGD catalysis, reverses hyperacetylation, represses malignant transcripts, and impairs metastatic tumorigenesis. We propose that PGD-driven suppression of TXNIP allows pancreatic cancers to avidly consume glucose. This renders PGD constitutively activated and enables metaboloepigenetic selection of additional traits that increase fitness along glucose-replete metastatic routes.
Highlights
Metastasis is the most common cause of cancer deaths, metastasis-intrinsic dependencies remain largely uncharacterized
To address this possibility experimentally, we took advantage of a unique panel of clonal cell lines and tumor tissues collected from pancreatic ductal adenocarcinoma (PDAC) patients by rapid autopsies[5,11]. These samples have been heavily utilized by us[28,29] and others[5,10,12,13,18] to investigate traits that evolve in PDAC patients, since matched tumor tissues are available from the same individual patient(s) and the cell lines represent sequence-verified subclones that retain the morphologic, genetic, epigenomic, transcriptomic, and phenotypic properties of the parental tissues from which they were derived[5,10,11,13,28]. This included matched phosphogluconate dehydrogenase (PGD)-dependent liver and lung metastatic subclones that diverged from a PGDindependent metastatic peritoneal deposit in one patient, a PGD-dependent primary tumor subclone that seeded distant metastasis in another patient, matched liver and lung metastases from yet another patient, and individual PGD-dependent metastases collected from additional patients[5,10,18,28,29]
In the rapid autopsy cohort, an intrinsic property of PGD dependence is constitutively elevated PGD catalytic rates (PGDhigh)[29]. This results in steady-state depletion of the PGD substrate (6-phosphogluconate: 6PG)[28], indicating that provision of 6PG is rate limiting for high catalysis[29]
Summary
Because 6PG is synthesized from glucose[29] and clinical experience with positron emission tomography imaging indicates that distant metastases avidly consume glucose in vivo[25], we hypothesized that PGDdependent PDACs might have evolved intrinsic mechanism(s) that allowed them to consume the excess glucose required to support high PGD catalysis To begin testing this hypothesis, we first verified that glucose consumption rates were recurrently elevated in the PGD-dependent subclones from the rapid autopsy cohort, as compared to a control panel of PGD-independent PDACs isolated from primary tumors (Supplementary Fig. 1b) and metastatic peritoneal deposits[28,29] (Fig. 1b).
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