Biology subjects

Lockhart, J.

Publications and source records attributed to Lockhart, J..

3 recordsLinked to original sources

bioRxiv2026

TAp63-regulated oncogenic long non-coding RNA-8 ( TROLL-8 ) regulates human breast cancer progression through CPT1A-mediated fatty acid oxidation

Metabolic reprogramming is a crucial hallmark of cancer, supporting tumor growth and adaptation to cellular stress. Although fatty acid oxidation (FAO) has emerged as an important regulator in cancer, the mechanisms that control the FAO machinery remain poorly understood. Here, we demonstrate that the TAp63-regulated long non-coding RNA TROLL-8 is a key regulator of FAO in breast cancer. Using metabolomics and protein microarray assays followed by immunoprecipitation-mass spectrometry, we mechanistically demonstrate that TROLL-8 binds the FAO enzyme CPT1A and promotes the formation of a complex with ACSL1 and VDAC1, thereby enabling efficient fatty acid processing. Loss of TROLL-8 destabilizes this complex, leading to impaired FAO, decreased metabolic fitness, and suppression of tumorigenic phenotypes, such as anchorage-independent growth. Notably, higher levels of CPT1A and VDAC1 are associated with worse survival in breast cancer patients. Given the emerging role of CPT1A in therapy resistance, these findings suggest that targeting TROLL-8 could be a promising approach to selectively disrupt the hyperactive FAO machinery in breast cancers and other tumor types that rely on FAO for their progression.

Cancer Biology↗

bioRxiv2026

Quinolinic acid phosphoribosyl transferase moonlights as an apoptosis regulator to empower lung cancer progression

Although nicotinamide adenine dinucleotide (NAD) metabolism is fundamental for cancer cell survival, the role of the de novo NAD biosynthetic pathway, particularly in non-small cell lung cancer (NSCLC), remains largely unknown. Here, we describe a non-canonical role for the rate-limiting enzyme in de novo NAD+ biosynthesis, quinolinate phosphoribosyltransferase (QPRT), in NSCLC progression. We show that QPRT is highly expressed in late-stage tumors and required for NSCLC growth; however, its suppression does not change NAD levels or elicit compensatory NAD biosynthetic activity. Instead, QPRT interacts with caspase-3 and suppresses its activation, protecting NSCLC cells from apoptosis. This reveals a moonlighting function for QPRT in apoptosis regulation independent of its enzymatic activity in tryptophan catabolism. Together, these findings, redefine QPRT as a protein with dual functionality and reveal it as a potential therapeutic target in NSCLC, highlighting the importance of non-canonical roles of metabolic enzymes in cancer biology. SignificanceThis study reveals that QPRT supports NSCLC progression by directly inhibiting caspase-3-mediated apoptosis independent of NAD biosynthesis, redefining its role and highlighting non-enzymatic functions of metabolic enzymes as therapeutic targets.

cancer biology↗

bioRxiv2025

Aging directs the differential evolution of KRAS-driven lung adenocarcinoma

Lung adenocarcinoma (LUAD), the most common histological subtype of lung cancer(1, 2), is a disease of the elderly, with an average age of diagnosis of about 70 years of age(3). Older age is associated with an increased incidence of KRAS-driven LUAD(4), a particularly deadly type of LUAD characterized by treatment resistance and relapse. Despite this, our understanding of how old age shapes KRAS-driven LUAD evolution remains incomplete. While the age-related increase in cancer risk was previously ascribed to the accumulation of mutations over time, we are now beginning to consider the role of host biology as an independent factor influencing cancer. Here, we use single-cell RNA-Sequencing of KP (KrasG12D/+; Trp53flox/flox) LUAD transplanted into young and old mice to define how old age affects LUAD evolution and map the changes that old age imposes onto LUADs microenvironment. Our data demonstrates that the aged lung environment steers LUAD evolution towards a primitive stem-like state that is associated with poor prognosis. We ascribe this differential evolution, at least in part, to a population of rare and highly secretory damage-associated alveolar differentiation intermediate (ADI) cells that accumulate in the aged tumor microenvironment (TME) and that dominate the niche signaling received by LUAD cells. Overall, our data puts aging center stage in coordinating LUAD evolution, highlighting the need to model LUAD in its most common context and creating a framework to tailor future cancer therapeutic strategies to the age of the patient to improve outcomes in the largest and most vulnerable LUAD patient population, the elderly.

cancer biology↗