Biology subjects

Abt, E. R.

Publications and source records attributed to Abt, E. R..

3 recordsLinked to original sources

bioRxiv2024

PGC-1α drives small cell neuroendocrine cancer progression towards an ASCL1-expressing subtype with increased mitochondrial capacity

Adenocarcinomas from multiple tissues can evolve into lethal, treatment-resistant small cell neuroendocrine (SCN) cancers comprising multiple subtypes with poorly defined metabolic characteristics. The role of metabolism in directly driving subtype determination remains unclear. Through bioinformatics analyses of thousands of patient tumors, we identified enhanced PGC-1--a potent regulator of oxidative phosphorylation (OXPHOS)--in various SCN cancers (SCNCs), closely linked with neuroendocrine differentiation. In a patient-derived prostate tissue SCNC transformation system, the ASCL1-expressing neuroendocrine subtype showed elevated PGC-1 expression and increased OXPHOS activity. Inhibition of PGC-1 and OXPHOS reduced the proliferation of SCN lung and prostate cancer cell lines and blocked SCN prostate tumor formation. Conversely, enhancing PGC- 1 and OXPHOS, validated by small-animal Positron Emission Tomography mitochondrial imaging, tripled the SCN prostate tumor formation rate and promoted commitment to the ASCL1 lineage. These results establish PGC-1 as a driver of SCNC progression and subtype determination, highlighting novel metabolic vulnerabilities in SCNCs across different tissues. STATEMENT OF SIGNIFICANCEOur study provides functional evidence that metabolic reprogramming can directly impact cancer phenotypes and establishes PGC-1-induced mitochondrial metabolism as a driver of SCNC progression and lineage determination. These mechanistic insights reveal common metabolic vulnerabilities across SCNCs originating from multiple tissues, opening new avenues for pan-SCN cancer therapeutic strategies.

cancer biology↗

bioRxiv2023

Targeting host deoxycytidine kinase attenuates Staphylococcus aureus virulence

Host-directed therapy (HDT) is an emerging approach to overcome antimicrobial resistance in pathogenic microorganisms. Specifically, HDT targets host-encoded factors required for pathogen replication and survival without interfering with microbial growth or metabolism, thereby eliminating the risk of resistance development. By applying HDT and a drug repurposing approach, we demonstrate that (R)-DI-87, a clinical-stage anti-cancer drug and potent inhibitor of mammalian deoxycytidine kinase (dCK), mitigates Staphylococcus aureus abscess formation in organ tissues upon invasive bloodstream infection. Mechanistically, (R)-DI-87 shields phagocytes from staphylococcal death-effector deoxyribonucleosides that target dCK and the mammalian purine salvage pathway-apoptosis axis. In this manner, (R)-DI-87-mediated protection of immune cells amplifies macrophage infiltration into deep-seated abscesses, a phenomenon coupled with enhanced pathogen control, ameliorated immunopathology, and reduced disease severity. Thus, pharmaceutical blockade of dCK represents an advanced anti-infective intervention strategy against which staphylococci cannot develop resistance and may help to fight fatal infectious diseases in hospitalized patients.

microbiology↗

bioRxiv2019

Defective Nucleotide Catabolism Defines a Subset of Cancers Sensitive to Purine Nucleoside Phosphorylase Inhibition

Small molecule inhibitors of purine nucleoside phosphorylase (PNP) have been explored as a treatment strategy for leukemia and lymphoma, however, the determinants of response to this class of drugs are incompletely understood. PNP inhibitors impair cell proliferation by preventing catabolism of the nucleoside deoxyguanosine (dG) which induces toxic imbalances amongst intracellular deoxyribonucleotide triphosphate (dNTP) pools following its phosphorylation and trapping by nucleoside kinases. We hypothesized that differential nucleoside uptake or catabolism defines cancer cell lines as either sensitive or resistant to PNP inhibition. Among cancer cell lines we found that T-cell acute lymphoblastic leukemia (T-ALL) cells are uniquely and acutely sensitive to PNP inhibition whereas the B-cell leukemia and solid tumor models are completely resistant. We determined that although the nucleoside scavenging kinase deoxycytidine kinase (dCK) was active in all cells tested, PNP inhibitors only induced dGTP pool increases in sensitive models. By evaluating the expression of key genes involved in nucleotide scavenging, biosynthesis, and phosphohydrolysis in a panel of sensitive and resistant cell lines we found that the dNTP phosphohydrolase SAM histidine aspartate containing protein 1 (SAMHD1) was exclusively expressed in resistant models. Using CRISPR/Cas9 SAMHD1 knockout cell lines, we verified that PNP inhibitor sensitivity is a function of SAMHD1 expression and determined that the pharmacological inhibition of dCK or genetic restoration of SAMHD1 conferred resistance to PNP inhibition. Importantly, we determined that low expression of SAMHD1 is not limited to T-ALL as subset of established and primary solid tumors models are SAMHD1-deficient. These solid tumor models were consistently acutely sensitive to PNP inhibitors which indicates that the utility of PNP inhibitors extends beyond hematological malignancies. Additionally, we found that deoxycytidine (dC) can limit the anti-proliferative effects of PNP inhibitors by competing with dG for phosphorylation by dCK but this effect can be overcome by expression of dC-catabolizing gene cytidine deaminase (CDA). Collectively, these results indicate that SAMHD1, dCK and CDA are critical biomarkers that must be used to stratify patients in clinical trials evaluating pharmacological PNP inhibition.

cancer biology↗