The 8th Tsuneko & Reiji Okazaki Award 2024 Winner

Identifying and exploiting the links between metabolism and cell state

Lydia Finley
Geoffrey Beene Junior Faculty Chair;
Associate Member, Cell Biology Program, Memorial Sloan Kettering Cancer Center;
Associate Professor, Weill Cornell Medical College

Cell survival and proliferation requires energy, reducing equivalents, and biosynthetic precursors required to maintain basic cellular processes. To meet these demands, cells take up and catabolize nutrients via an intricate network of metabolic pathways. Despite requiring a fixed set of metabolic intermediates to maintain homeostasis and increase biomass, mammalian cells exhibit notable metabolic flexibility and heterogeneity. In this presentation, I will discuss our recent research demonstrating how cell identity is a major driver of metabolic heterogeneity. As cells transit through normal or malignant development, acquisition of different cell identities is accompanied by metabolic remodeling that is often required for successful cell state transitions. Reciprocally, intracellular metabolites can directly regulate cell fate transitions, in part by regulating chromatin modifications that shape gene expression programs. In this manner, cell metabolism is an intrinsic component of the establishment and maintenance of different cell types. My presentation will focus on our latest work on how cell-type specific metabolic profiles are established and the functional consequences of changes in metabolic wiring upon cell fate transitions in normal development and disease.

Reference

1. Arnold TCA Arnold PK, Jackson BT, Paras KI, Brunner JS, Hart ML, Newsom OJ, Alibeckoff SP, Endress J, Drill E, Sullivan LB, Finley LWS. A non-canonical tricarboxylic acid cycle underlies cellular identity. Nature. 603: 477-481, 2022.


2. Baksh SC, Todorova PK, Gur-Cohen S, Hurwitz B, Novak SS, Tierney MT, Racelis J, Fuchs E^#, Finley LWS^#. Extracellular serine availability determines epidermal stem cell fate and tumor initiation. Nat Cell Biol. 22: 779-790, 2020. (^#co-corresponding author.)


3. Morris JP 4th^*, Yashinskie JJ^*, Koche R, Chandwani R, Tian S, Chen CC, Baslan T, Marinkovic ZS, Sánchez-Rivera FJ, Leach SD, Carmona-Fontaine C, Thompson CB, Finley LWS^#, Lowe SW^#. α-Ketoglutarate links p53 to cell fate during tumour suppression. Nature. 573: 595-599, 2019.


4. Carey BW^*, Finley LW^* (equal contribution), Cross JR, Allis CD, Thompson CB. Intracellular α-ketoglutarate maintains the pluripotency of embryonic stem cells. Nature. 518: 413-416, 2015.


5. Jackson BT, Finley LWS. Metabolic regulation of the hallmarks of stem cell biology. Cell Stem Cell. 31: 161-180, 2024.

Award Lecture