Tumor cells display metabolic profiles that are remarkably distinct from their tissue of origin to ensure fulfillment of their bioenergetic and biosynthetic needs to support rapid proliferation. The main goal of this study was to determine the functional role of distinct utilization of serine metabolism to lung adenocarcinomas. We identified a metabolic subtype, described by PHGDH, with poor prognosis that display with unique metabolic dependencies (Zhang et al. Cell Reports, 2017).
To investigate the potential relevance of metabolic diversity in lung adenocarcinomas, we examined the expression of multiple metabolic enzymes in 720 lung adenocarcinoma patients across 9 cohorts. Our Kaplan-Meier analysis showed that high expression of phosphoglycerate dehydrogenase (PHGDH), the rate-limiting enzyme in de novo serine biosynthesis, was associated with poor prognosis. Additional, tissue-micro array analyses of primary tumor biopsies and matched adjacent normal tissues revealed that PHGDH expression is markedly and significantly elevated in tumor samples of lung adenocarcinoma compared to the adjacent healthy tissues, allowing a therapeutic window. The TMA analysis uncovered that the tumor samples diverge into high and low expressing PHGDH primary adenocarcinomas. To characterize the relevance of PHGDH and the serine pathway in lung adenocarcinomas, we evaluated the endogenous expression level across a cell line panel consisting of lung tumor cell lines as well as normal lung cells. These analyses confirmed that the PHGDH expression is elevated in tumor cells compared to normal cells although some tumor express low levels of the enzyme. The normal cells barely expressed the enzymes of the serine pathway, concordant to the data obtained from tumor biopsies.
By undertaking an integrative approach, based on metabolomics, proteomics and genetics we have dissected the metabolic fingerprints of lung adenocarcinomas, and we show that PHGDH, the rate-limiting enzyme in serine biosynthesis, is highly expressed in a adenocarcinoma subset with poor prognosis. This subset harbors a gene signature for DNA replication and proliferation. Accordingly, models with high levels of PHGDH display rapid proliferation and high migratory capacity. PHGDH-high tumors displayed a more rapid growth in vivo compared to the tumors with low expression. Importantly, depletion of PHGDH displayed selective toxicity to the PHGDH-high cancer cells. PHGDH-high cells displayed a unique metabolic program including selective channeling of serine-derived carbons to boost the antioxidant defense eg. Glutathione biosynthesis. Serine was beyond this also utilized for production of nucleotides and nucleosides. Consequently, genetic depletion of PHGDH rendered in a deficiency of nucleotides/nucleosides causing DNA damage. Thus, serine metabolism is coupled to DNA stability in the PHGDH-high metabolic subtype.
Combined, our study provides evidence that a unique metabolic program is activated in a lung adenocarcinoma subset, described by PHGDH, which confers growth and survival and may have therapeutic implications.
We are now continuing our studies aiming to understand the mechanisms behind a differential PHGDH protein expression.
Original Publications during grant period:
1. Zhang B, Zheng A, Hydbring P, Ambroise G, Ouchida AT, Goiny M, Vakifahmetoglu-Norberg, H, NORBERG E. PHGDH Defines a metabolic subtype in lung adenocarcinomas with poor prognosis.
Cell Reports 2017, 13;19(11):2289-2303.
>Our article was selected as ‘Issue Highlight’ by Cell Reports.
2. Zhang B, Tornmalm J, Widengren J, Vakifahmetoglu-Norberg H, NORBERG E. Characterization of the Role of the Malate Dehydrogenases to Lung Tumor Cell Survival. Journal of Cancer, 2017, 8(11):2088-2096.
3. Eriksson M, Ambroise G, Ouchida A, Smith D, Gimenez-Cassina A, Iwanicki M, Muller P, NORBERG E#, and Vakifahmetoglu-Norberg H#. Effect of Mutant p53 Proteins on Glycolysis and Mitochondrial Metabolism.
Mol Cell Biol 2017 Nov 28;37(24). pii: e00328-17.
# co-corresponding author.
>Our article was selected for the Cover by Mol Cell Biol (December 2017, Volume 37, Number 24)
4. Queiroz AL, Zhang B, Comstock DE, Hao Y, Eriksson M, Hydbring P, Vakifahmetoglu-Norberg H, NORBERG E. mir-126-5p Targets Malate Dehydrogenase 1 in Non-Small Cell Lung Carcinomas. Biochem Biophys Res Commun, 2018 May 5;499(2):314-320.
Reviews and Ediorials during grant period:
5. Queiroz Lima A, Vakifahmetoglu-Norberg H, NORBERG E. Resistant to Targeted Therapies – Aim for Metabolic Liabilities.
Theranostics. 2018 Jan 2;12(1):1-222
6. Vakifahmetoglu-Norberg H, Ouchida A, NORBERG E. The role of mitochondria in metabolism and Cell death. (2017) 15;482(3):426-431