Schug Research

Hlavaty SI, Salcido KN, Pniewski KA, Ma W, Kannan T, Mukha D, Srikanth YVV, Salvino JM, Liu Q, Kossenkov A, Chen Q, Schug ZT. ACSS1-dependent acetate metabolism rewires mitochondrial metabolism to support AML and melanoma tumor growth and metastasis. Cell Reports, Dec 24;43(12):1149882024.

• This study demonstrates that when cancer cells with high expression of ACSS1 are exposed to acetate it causes significant metabolic rewiring that promotes cancer cell survival and tumor growth. These studies highlight the potential for targeting ACSS1 in select cancer types.

Mukha D, Dessain J, O’Connor S, Pniewski K, Bertolazzi F, Schug ZT.  Identification of Fasnall as a therapeutically effective Complex I inhibitor. bioRxiv [Preprint]. 2024 May 6:2024.05.03.592013. doi: 10.1101/2024.05.03.592013.

• This study used metabolomics to generate a robust biomarker profile associated with fatty acid synthase (FASN) inhibition. Examination of this profile showed that several previously described FASN-targeting pharmacological agents do not inhibit FASN in cells and identified one of these agents as a novel mitochondrial Complex I inhibitor.

Miller KD, O’Connor S, Pniewski K, Kannan T, Acosta R, Mirji G, Papp S, Hulse M, Mukha D, Hlavaty S, Salcido KN, Bertolazzi F, Srikanth YVV, Zhao S, Wellen KE, Shinde RS, Claiborne DT, Kossenkov A, Salvino JM, Schug ZT. Acetate acts as a metabolic immunomodulator by bolstering T cell effector function and potentiating anti-tumour immunity in breast cancer. Nat Cancer. Oct; 4(10):1491-1507, 2023.

• We showed that targeting ACSS2 promotes an antitumor immune response and enhances the efficacy of chemotherapy in preclinical breast cancer models. These findings established a new paradigm for targeting acetate metabolism in cancer in which inhibition of ACSS2 dually acts to impair tumor cell metabolism and potentiate anti-tumor immunity.

Miller KD, Pniewski K, Perry CE, Papp SB, Shaffer JD, Velasco-Silva JN, Casciano JC, Aramburu TM, Srikanth Y.V.V., Cassel J, Skordalakes E, Kossenkov AV, Salvino JM, and Schug ZT. Targeting ACSS2 with a transition state mimetic inhibits triple negative breast cancer growth. Cancer Res. Mar 1;81(5):1252-1264, 2021.

• In this study, we synthesized a small-molecule inhibitor that acts as a transition-state mimetic to block ACSS2 activity in vitro and in vivo. Pharmacologic inhibition of ACSS2 as a single agent impaired breast tumor growth. Collectively, our findings suggest that targeting ACSS2 may be an effective therapeutic approach for the treatment of patients with breast cancer.

Schug ZT, Peck B, Zhang Q, Jones DT, Grosskurth S, Alam IS, Smethurst E, Mason S, Blyth K, McGarry L, James D, Shanks E, Kalna G, Saunders B, Jiang M, Howell M, Lassailly F, Thin MZ, Spencer-Dene B, Stamp G, Harris AL, Aboagye EO, Critchlow SE, Wakelam MJO, Schulze A, Gottlieb E. Acetyl-CoA Synthetase 2 promotes acetate utilization and maintains cancer cell growth under metabolic stress. Cancer Cell. Jan 12; 27(1):57-71, 2015. Notes: Highlighted in Nature Reviews Cancer and Cancer Discovery.

• We found that nearly 40% of invasive ductal carcinoma have high expression of acetyl-CoA synthetase 2 (ACSS2). ACSS2, an enzyme that converts acetate to acetyl-CoA, imparts a competitive growth advantage under conditions of metabolic stress by enhancing the ability of cancer cells to use acetate as an additional nutritional source when other carbon sources are scarce or cannot be used to sustain fatty acid production. This study also identified ACSS2 as a potential molecular target for managing cancer growth.