Biology subjects

Ilter, D.

Publications and source records attributed to Ilter, D..

6 recordsLinked to original sources

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↗

bioRxiv2024

Methylmalonic acid induces metabolic abnormalities and exhaustion in CD8+ T cells to suppress anti-tumor immunity

Systemic levels of methylmalonic acid (MMA), a byproduct of propionate metabolism, increase with age and MMA promotes tumor progression via its direct effects in tumor cells. However, the tumorigenic role of MMA in modulating the tumor ecosystem remains to be investigated. The proliferation and function of CD8+ T cells, key anti-tumor immune cells, declines with age and in conditions of vitamin B12 deficiency, the two most well-established conditions that lead to increased systemic levels of MMA. Thus, we hypothesized that increased circulatory levels of MMA leads to suppression of CD8+ T cell immunity. Treatment of primary CD8+ T cells with MMA induced a dysfunctional phenotype characterized by a robust immunosuppressive transcriptional reprogramming and marked increases in the expression of the exhaustion regulator, TOX. Accordingly, MMA treatment upregulated exhaustion markers in CD8+ T cells and decreased their effector functions, which drove the suppression of anti-tumor immunity in vitro and in vivo. Mechanistically, MMA-induced CD8+ T cell exhaustion was associated with a suppression of NADH-regenerating reactions in the TCA cycle and concomitant defects in mitochondrial function. Thus, MMA has immunomodulatory roles, thereby highlighting MMA as an important link between aging, immune dysfunction, and cancer.

immunology↗

bioRxiv2023

Interactions between ploidy and resource availability shape clonal interference at initiation and recurrence of glioblastoma

Glioblastoma (GBM) is the most aggressive form of primary brain tumor. Complete surgical resection of GBM is almost impossible due to the infiltrative nature of the cancer. While no evidence for recent selection events have been found after diagnosis, the selective forces that govern gliomagenesis are strong, shaping the tumors cell composition during the initial progression to malignancy with late consequences for invasiveness and therapy response. We present a mathematical model that simulates the growth and invasion of a glioma, given its ploidy level and the nature of its brain tissue micro-environment (TME), and use it to make inferences about GBM initiation and response to standard-of-care treatment. We approximate the spatial distribution of resource access in the TME through integration of in-silico modelling, multi-omics data and image analysis of primary and recurrent GBM. In the pre-malignant setting, our in-silico results suggest that low ploidy cancer cells are more resistant to starvation-induced cell death. In the malignant setting, between first and second surgery, simulated tumors with different ploidy compositions progressed at different rates. Whether higher ploidy predicted fast recurrence, however, depended on the TME. Historical data supports this dependence on TME resources, as shown by a significant correlation between the median glucose uptake rates in human tissues and the median ploidy of cancer types that arise in the respective tissues (Spearman r = -0.70; P = 0.026). Taken together our findings suggest that availability of metabolic substrates in the TME drives different cell fate decisions for cancer cells with different ploidy and shapes GBM disease initiation and relapse characteristics.

cancer biology↗

bioRxiv2022

NADK upregulation is an essential metabolic adaptation that enables breast cancer metastatic colonization

Metabolic reprogramming and metabolic plasticity allow cancer cells to fine-tune their metabolism to adapt to the ever-changing environments of the metastatic cascade, for which lipid metabolism and oxidative stress are of particular importance. Continuous production of NADPH, a cornerstone of both lipid and redox homeostasis, is essential for proliferation and cell survival suggesting that cancer cells may require larger pools of NADPH to efficiently metastasize. NADPH is recycled through reduction of NADP+ by several enzymatic systems in cells; however, de novo NADP+ is synthesized only through one known enzymatic reaction, catalysed by NAD+ kinase (NADK). Here, we show that NADK is upregulated in metastatic breast cancer cells enabling de novo production of NADP(H) and the expansion of the NADP(H) pools thereby increasing the ability of these cells to adapt to the oxidative challenges of the metastatic cascade and efficiently metastasize. Mechanistically, we found that metastatic signals lead to a histone H3.3 variant-mediated epigenetic regulation of the NADK promoter, resulting in increased NADK levels in cells with metastatic ability. Together, our work presents a previously uncharacterized role for NADK as an important contributor to breast cancer progression and suggests that NADK constitutes an important and much needed therapeutic target for metastatic breast cancers.

cancer biology↗

bioRxiv2020

Age-induced methylmalonic acid accumulation promotes tumor progression and aggressiveness

From age 65 onwards, the risk of cancer incidence and associated mortality is substantially higher1-3. Nonetheless, our understanding of the complex relationship between age and cancer is still in its infancy4. For decades, the link has largely been attributed to increased exposure time to mutagens in older individuals. However, this view does not account for the well-established role of diet, exercise and small molecules that target the pace of metabolic aging5-8. Here, we show that metabolic alterations that occur with age can render a systemic environment favorable to progression and aggressiveness of tumors. Specifically, we show that methylmalonic acid (MMA), a by-product of propionate metabolism, is significantly up-regulated in the serum of older people, and functions as a mediator of tumor progression. We traced this to the induction of SOX4 and a consequent transcriptional reprogramming that can endow cancer cells with aggressive properties. Thus, accumulation of MMA represents a novel link between aging and cancer progression, implicating MMA as a novel therapeutic target for advanced carcinomas.

cancer biology↗