Biology subjects

Drapela, S.

Publications and source records attributed to Drapela, S..

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

Targeting the dependence on PIK3C3-mTORC1 signaling in dormancy-prone breast cancer cells blunts metastasis initiation

Halting breast cancer metastatic relapses following primary tumor removal and the clinical dormant phase, remains challenging, due to a lack of specific vulnerabilities to target during dormancy. To address this, we conducted genome-wide CRISPR screens on two breast cancer cell lines with distinct dormancy properties: 4T1 (short-term dormancy) and 4T07 (prolonged dormancy). We discovered that loss of class-III PI3K, Pik3c3, revealed a unique vulnerability in 4T07 cells. Surprisingly, dormancy-prone 4T07 cells exhibited higher mTORC1 activity than 4T1 cells, due to lysosome-dependent signaling occurring at the cell periphery. Pharmacological inhibition of Pik3c3 counteracted this phenotype in 4T07 cells, and selectively reduced metastasis burden only in the 4T07 dormancy-prone model. This mechanism was also detected in human breast cancer cell lines in addition to a breast cancer patient-derived xenograft supporting that it may be relevant in humans. Our findings suggest dormant cancer cell-initiated metastasis may be prevented in patients carrying tumor cells that display PIK3C3-peripheral lysosomal signaling to mTORC1. Statement of SignificanceWe reveal that dormancy-prone breast cancer cells depend on the class III PI3K to mediate a constant peripheral lysosomal positioning and mTORC1 hyperactivity. Targeting this pathway might blunt breast cancer metastasis.

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↗

bioRxiv2021

Pre-existing cell subpopulations in primary prostate cancers display surface fingerprint of docetaxel-resistant cells

BackgroundDocetaxel resistance represents a leading obstacle in the therapy of prostate cancer (PCa), resulting in lethal disease. Intratumoral heterogeneity, which is frequently driven by epithelial-mesenchymal plasticity significantly contributes to the limited treatment response, chemoresistance, and subsequent poor prognosis of patients with lethal PCa. MethodsWe employed a high-throughput flow cytometry screening to identify cell surface fingerprint that associates with docetaxel resistance in PCa cells. Using patient-derived xenografts, we validated protein expression of the most robustly changed antigens in vivo and further assessed this 6-molecule surface fingerprint in primary PCa tumors. ResultsWe revealed the overexpression of SSEA-4 antigen in both in vitro and in vivo docetaxel-resistant models and confirmed the SSEA-4 enrichment in a subpopulation of freshly isolated primary PCa tumors. The level of ST3GAL2, an enzyme that is critically involved in the SSEA-4 synthesis, correlated with increased expression of CD44, CD59, and CD95 and reduced expression of EpCAM and CD9. SSEA-4 was further directly linked to the antimicrotubule agent resistance and poor prognosis in PCa patients. ConclusionsWe propose that the 6-molecule surface fingerprint associates with docetaxel resistance and pre-exists in a cell subpopulation of primary PCa tumors even before docetaxel treatment.

cancer biology↗