Metabolic reprogramming during senescence

Cellular senescence is tumor suppressive and also plays an important role in aging phenotypes. We know that senescent cells show a marked reprograming of metabolism; however, how this contributes to tumor suppression and/or aging remains unclear. Current projects in the lab focus on: 1) the role of nucleotide metabolism in overcoming senescence to lead to cancer; 2) the role of TCA cycle metabolism in the epigenetic control of senescence; 3) the role of metabolism in regulation of the senescence-associated secretory phenotype (SASP).

See the following publications for more detail:

Buj R, et al. Suppression of p16 increases nucleotide synthesis via mTORC1. Cell Reports. 2019 Aug 20; 28(8):1971-1980.

Aird KM, et al ATM couples replication stress and metabolism reprogramming during cellular senescence. Cell Reports. 2015 May;11(6):893-901.

Aird KM and Zhang R. Metabolic alterations accompanying oncogene-induced senescence. Molecular & Cellular Oncology, 2014;1(3).

Aird KM and Zhang R. Nucleotide Metabolism, Oncogene-Induced Senescence and Cancer. Cancer Letters. 2014 Jan 28;356(2 Pt A):204-10.

Aird KM et al. Suppression of nucleotide metabolism underlies the establishment and maintenance of oncogene-induced senescence. Cell Reports. 2013 Apr 25;3(4):1252-65.

 
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Nucleotide metabolism in disease

Homeostasis of nucleotide metabolism is critical for the health of cells. We are interested in understanding novel pathways that regulate nucleotide metabolism and whether nucleotide biosynthesis is a metabolic vulnerability for some cancer cells. Current projects include: 1) the interplay between the cell cycle and nucleotide metabolism; 2) ATR-mTORC1-mediated nucleotide metabolism in cancer cells with low p16; and 3) the cross-talk between nucleotide metabolism and the tumor microenvironment.

See the following publications for more detail:

Buj, R, et al. Suppression of p16 increases nucleotide synthesis via mTORC1. Cell Reports. 2019 Aug 20; 28(8):1971-1980.

Buj R and Aird KM. dNTP Metabolism in Cancer and Metabolic Disease. dNTP Metabolism in Cancer and Metabolic Disease. Front Endocrinol (Lausanne). 2018 Apr 18;9:177.

Fatkhudinov N, et al. Targeting ribonucleotide reductase M2 and mutant BRAF is a novel combinatorial strategy for melanoma.  Mol Cancer Res. 2016 Sep;14(9):767-75.

Aird KM, et al. ATM couples replication stress and metabolism reprogramming during cellular senescence. Cell Reports. 2015 May;11(6):893-901.

Aird KM and Zhang R. Metabolic alterations accompanying oncogene-induced senescence. Molecular & Cellular Oncology, 2014;1(3).

Aird KM and Zhang R. Nucleotide Metabolism, Oncogene-Induced Senescence and Cancer. Cancer Letters. 2014 Jan 28;356(2 Pt A):204-10.

Aird KM, et al. Suppression of nucleotide metabolism underlies the establishment and maintenance of oncogene-induced senescence. Cell Reports. 2013 Apr 25;3(4):1252-65.

 
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Exploiting metabolic vulnerabilities for ovarian cancer therapy

Ovarian cancer remains the most lethal gynecological malignancy. This is mostly due to resistance of ovarian cancer to the current therapies. Ovarian cancer cells have marked changes in cellular metabolism. Therefore, we may be able to exploit these metabolic vulnerabilities for improved response to therapy. Current projects include: 1) elucidation of metabolic reprogramming in ovarian cancer stem cells and novel combination treatment strategies; 2) dissection of metabolic changes in adherent vs. non-adherent conditions; and 3) identification of novel metabolic inhibitors in combination with ATM inhibitors, which are currently poised for clinical trials.

See the following publications for more detail:

Dahl ES, et al.Targeting IDH1 as a pro-senescent therapy for high grade serous ovarian cancer. Mol Cancer Res. 2019 Aug;17(8):1710-1720.

Buj, R, et al. Suppression of p16 increases nucleotide synthesis via mTORC1. Cell Reports. 2019 Aug 20; 28(8):1971-1980.

Dahl ES and Aird KM.Ataxia-Telangiectasia Mutated Modulation of Carbon Metabolism in Cancer. Frontiers in Oncology. 2017 Nov 29;7:291.

Aird KM, et al. Identification of ribonucleotide reductase M2 as a potential target for pro-senescence therapy in epithelial ovarian cancer. Cell Cycle. 2013 Oct 29;13(2).

 
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