Research
Regulation of cellular metabolism, and its dysregulation in disease
The Possemato lab studies regulation of cellular metabolism in mammalian systems and the dysregulation of metabolism in disease states. To this end, we focus on three key areas.
01
Iron-sulfur cluster metabolism and iron sensing pathways
Iron-sulfur clusters are essential protein cofactors whose dysregulation is linked to a wide range of diseases, including Friedreich's Ataxia. We use cellular and mouse models of iron-sulfur cluster dysfunction to understand the physiological importance of these pathways, with a particular focus on their role in the iron-sensing apparatus.
02
Identifying novel cancer therapies for triple-negative breast cancer
Triple-negative breast cancer (TNBC) is a clinically aggressive breast cancer subset with limited effective targeted therapies. We identified a differential requirement for iron-sulfur cluster biosynthesis in TNBC cells, driven by a selective requirement for POLE — an iron-sulfur cluster-containing protein and the catalytic subunit of the leading-strand replicative polymerase. We are evaluating POLE as an actionable target in TNBC.
03
Tumor environment–cell metabolic interactions and selective vulnerabilities
Cells within a tumor are frequently starved for nutrients, owing to a combination of increased consumption and unreliable vasculature. We run genetic screens in nutrient-limited environments to delineate the impact of nutrient limitation on gene requirement. Current work focuses on how modulating de novo pyrimidine synthesis affects apoptosis, immune cell function, and response to therapy, as well as the importance of cysteine metabolism to iron-dependent cell death (ferroptosis).
Key findings
From recent publications
Nam et al, Nature Metabolism, 2024 Nov 26
- Chemotherapeutic agents targeting de novo pyrimidine synthesis have reduced anti-cancer activity at tumor-relevant glucose concentrations.
- Inhibiting de novo pyrimidine synthesis causes replication fork stalling and apoptosis through the intrinsic (mitochondrial) pathway.
- Glucose promotes shunting of pyrimidines to nucleotide sugar synthesis, increasing the effectiveness of chemotherapeutics that target early steps in de novo pyrimidine synthesis.
- Glucose promotes execution of apoptosis triggered by inhibiting replication.
- UCK1, UCK2, and UCK1L each have uridine cytidine kinase activity; we generated a model lacking this activity by deleting all three genes and expressing a catalytically inactive UCK2 mutant.
Shin et al, Nature Metabolism, 2023 Jan 6
nature.com/articles/s42255-023-00735-9
- CAD activity fluctuates during the cell cycle, peaking in S phase.
- UTP levels change during the cell cycle, opposite to CAD activity.
- Changes in CAD activity are explained by allosteric inhibition by UTP, not by phosphorylation or growth-factor-driven oligomerization.
- Two flexible loops in the CAD allosteric domain evolved in animals to mediate regulation by UTP.
- UTP binding regulates formation of a substrate channel that permits catalytic activity, mediated by a transmission loop.
Terzi et al, Science Advances, 2021 May 26
doi.org/10.1126/sciadv.abg4302
- Inhibiting iron-sulfur cluster (ISC) synthesis triggers ferroptosis sensitivity in cancer cells that upregulate the transferrin receptor.
- IRP1 is dispensable for altered iron metabolism upon ISC inhibition.
- IRP2 stability upon ISC inhibition depends on environmental oxygen, independent of IRP1.
- Cells lacking both IRP1 and IRP2 are resistant to ferroptosis, even when ISC synthesis is inhibited.
Sviderskiy et al, Molecular Cell, 2020 Nov 19
- Basal-like breast cancer (BLBC) cells are especially sensitive to suppression of ISC biosynthesis, compared to other breast cancer subtypes.
- POLE1 requires ISC cofactor binding to support replication; BLBC is selectively susceptible to its partial suppression.
- Suppression of POLE1 causes DNA damage, inflammatory cytokine expression, and senescence or cell death, selectively in BLBC cells.
- Hyperactive CDK2 may underlie BLBC sensitivity to ISC or POLE1 suppression — and a therapeutic liability worth targeting.
Alvarez and Sviderskiy et al, Nature, 2017 Nov 30
nature.com/articles/nature24637
- Cancer cells in culture are more sensitive to suppression of oxygen-utilizing enzymes than the same cells in a tumor — tissue-level oxygen culture better mimics in vivo conditions.
- NFS1, a critical enzyme in iron-sulfur cluster biosynthesis, is upregulated in lung adenocarcinoma and under high oxygen.
- Suppressing ISC biosynthesis activates the iron-starvation response and increases sensitivity to ferroptosis.
Selected awards
Recognition
- 2019 Above and Beyond Mentorship Award
- 2018 AACR NextGen Star
- 2016 Pew-Stewart Scholar for Cancer Research
- 2015 Susan G. Komen Career Catalyst
- 2015 V Foundation V Scholar Award
- 2012 K99/R00 Transition to Independence Award, NIH
- 2011 Margaret and Herman Sokol Post-Doctoral Award, Whitehead Institute
- 2009 Susan G. Komen Post-Doctoral Fellowship
- 2002 Howard Hughes Medical Institute Pre-Doctoral Fellowship