Better explicating the strengths and shortcomings of these models will help refine projections and improve transparency in the years ahead.
Image credit: Witsawat.S.
Edited by David A. Tuveson, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, and accepted by Editorial Board Member Anton Berns January 14, 2021 (received for review June 19, 2020)
Significance
A hallmark of pancreatic ductal adenocarcinoma (PDAC) is its extensively reprogrammed metabolic network, in which NAD and its reduced form NADH are critical cofactors. Here, we show that IFN signaling, present in a subset of PDAC tumors, increases consumption of NAD(H) through upregulation of PARP9, PARP10, and PARP14. This NAD(H) consumption results in increased dependence upon NAMPT for the recycling of NAM to salvage NAD pools, thus sensitizing these tumor cells to treatment with pharmacologic NAMPT inhibition by decreasing PDAC cell proliferation and invasion in vitro and suppressing orthotopic tumor growth and liver metastases in vivo through this mechanism.
Abstract
Emerging evidence suggests that intratumoral interferon (IFN) signaling can trigger targetable vulnerabilities. A hallmark of pancreatic ductal adenocarcinoma (PDAC) is its extensively reprogrammed metabolic network, in which nicotinamide adenine dinucleotide (NAD) and its reduced form, NADH, are critical cofactors. Here, we show that IFN signaling, present in a subset of PDAC tumors, substantially lowers NAD(H) levels through up-regulating the expression of NAD-consuming enzymes PARP9, PARP10, and PARP14. Their individual contributions to this mechanism in PDAC have not been previously delineated. Nicotinamide phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme in the NAD salvage pathway, a dominant source of NAD in cancer cells. We found that IFN-induced NAD consumption increased dependence upon NAMPT for its role in recycling NAM to salvage NAD pools, thus sensitizing PDAC cells to pharmacologic NAMPT inhibition. Their combination decreased PDAC cell proliferation and invasion in vitro and suppressed orthotopic tumor growth and liver metastases in vivo.
Footnotes
↵1A.M.M. and L.Z. contributed equally to this work.
- ↵2To whom correspondence may be addressed. Email: cradu{at}mednet.ucla.edu or tdonahue{at}mednet.ucla.edu.
Author contributions: A.M.M., L.Z., J.C., L.L., N.W., E.R.A., R.G., I.E., A.M.D., C.G.R., and T.R.D. designed research; A.M.M., L.Z., J.C., L.L., N.W., A.Y., S.P., K.L., E.R.A., S.K., R.G., N.K., K.P., I.E., A.M.D., R.R., T.L., D.W.D., and T.R.D. performed research; E.R.A., R.R., T.L., and D.W.D. contributed new reagents/analytic tools; A.M.M., L.Z., J.C., L.L., N.W., S.P., K.L., E.R.A., S.K., R.G., R.R., T.L., C.G.R., and T.R.D. analyzed data; and A.M.M., L.Z., C.G.R., and T.R.D. wrote the paper.
Competing interest statement: C.G.R. is a cofounder of Sofie Biosciences and Trethera Corporation. He and the University of California (UC) hold equity in Sofie Biosciences and Trethera Corporation. The intellectual property developed by C.G.R. and licensed by UC to Sofie Biosciences and Trethera Corporation was not used in this study.
This article is a PNAS Direct Submission. D.A.T. is a guest editor invited by the Editorial Board.
This article contains supporting information online at https://www.pnas.org/lookup/suppl/doi:10.1073/pnas.2012469118/-/DCSupplemental.
Data Availability
All study data are included in the article and/or supporting information.
Published under the PNAS license.
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NAD+ depletion by type I interferon signaling sensitizes pancreatic cancer cells to NAMPT inhibition
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