Growth Signaling Research Articles

Biomechanical changes occur in myopic choroidal stroma and mirror those in the adjacent sclera

Retina-derived growth signals relayed from the choroid to the sclera cause remodeling of the extracellular scleral matrix, resulting in myopic ocular elongation. However, to the best of our knowledge, no studies have assessed changes in choroidal stromal biomechanical properties during myopia progression. Here we utilized 7 µm-resolution scanning acoustic microscopy (SAM) to assess biomechanical properties (bulk modulus (K) and mass density (rho)) of choroidal stroma from guinea pig eyes with form-deprivation (FD) induced myopia. The choroidal stroma had considerable intrinsic strength arising from its biomechanical properties and these were differentially affected by myopia in central and peripheral regions. Choroidal stromal biomechanical values were also highly correlated with those in adjacent scleral regions, and the choroidal stromal-scleral association was stronger in myopic eyes. Biomechanical changes observed in the choroidal stroma of myopic eyes were mirrored to those observed in the adjacent sclera. These findings suggest that choroidal stromal remodeling may accompany myopia and open the door to the source of the signals that cause scleral remodeling in myopia.

Synergistic Phytochemical and Pharmacological Actions of Hair RiseTM Microemulsion: A Novel Herbal Formulation for Androgenetic Alopecia and Hair Growth Stimulation.

Androgenetic alopecia (AGA) is a genetic condition characterized by an excessive response to androgens, leading to hairline regression in men and hair thinning at the vertex in women, which can negatively impact self-esteem. Conventional synthetic treatments for AGA are often limited by their side effects. In contrast, Thai medicinal plants offer a promising alternative with fewer adverse effects. This study investigates the synergistic phytochemical and pharmacological effects of a novel Hair RiseTM microemulsion, formulated with bioactive extracts from rice bran (Oryza sativa), shallot bulb (Allium ascalonicum), licorice root (Glycyrrhiza glabra), and corn kernels (Zea mays), for the treatment of hair loss. The microemulsion, in concentrations of 50%, 75%, and 100% (v/v), significantly enhanced the proliferation of human hair follicle dermal papilla cells (HFDPCs) compared to minoxidil. Additionally, it upregulated critical hair growth signaling pathways, including Wnt/β-catenin (CTNNB1), Sonic Hedgehog (SHH, SMO, GLI1), and vascular endothelial growth factor (VEGF), surpassing standard controls such as minoxidil and purmorphamine. The microemulsion also demonstrated potent anti-inflammatory and antioxidant properties by reducing nitric oxide production and oxidative stress, factors that contribute to inflammation and follicular damage in AGA. Furthermore, Hair RiseTM inhibited 5α-reductase (types 1-3), a key enzyme involved in androgen metabolism, in both human prostate cancer cells (DU-145) and HFDPCs. These findings suggest that Hair RiseTM microemulsion presents a promising natural therapy for promoting hair growth and reducing hair loss via multiple synergistic mechanisms, offering a potent, plant-based alternative to synthetic treatments.

Flexible substrate-based mass spectrometry platform for in situ non-destructive molecular imaging of living plants.

Monitoringand localizing molecules on living plants is critical for understanding their growth, development and disease. However, current techniques for molecular imaging of living plants often lack spatial information or require tedious pre-labelling. Here, we proposed a novel molecular imaging platform that combines sliver nanowire-doped Ti3C2 MXene (AgNWs@MXene) flexible film substrate with laser desorption/ionization mass spectrometry imaging (AMF-LDI-MSI) to study the spatial distribution of biomolecules on the surface of living plants. This platform overcomes the MSI challenges posed by difficult-to-slice plant tissues (e.g., tough or water-rich roots and fragile flowers) and enables precisely transfer and visualize the molecule. Comparisons of the measurement results to those from matrix-assisted LDI-MSI (MALDI-MSI) technology demonstrate the accuracy and reliability of the platform. Biocompatibility evaluations indicated that the platform without observable adverse effects on the health of living plants. The distribution of growth and disease-associated signalling molecules, such as choline, organic acids and carbohydrates, can be in situ non-destructively detected on the surfaces of living plants, which is important for tracking the health of plants and their diseased areas. AMF-LDI-MSI platform can serve as a promising tool for label-free, in situ and non-destructive monitoring of functional biomolecules and plant growth from a spatial perspective.

Genome-wide identification and gene expression networks of LBD transcription factors in Populus trichocarpa

The Lateral Organ Boundaries Domain (LBD) proteins, an exclusive family of transcription factors (TFs) found solely in plants, play pivotal roles in lateral organogenesis, stress adaptation, secondary growth, and hormonal signaling responses. In this study, a total of 55 PtLBD TFs from Populus trichocarpa were identified and systematically classified into two subfamilies, designated as subfamily-I and subfamily-II with seven distinct groups based on phylogenetic analysis. Gene structure detection indicated that the difference of phase numbers linking adjacent exons contribute to the variations in splicing patterns among different PtLBD groups. Numerous transcription factor binding sites and cis-elements pertinent to hormone signaling pathways and stress response mechanisms were identified within the upstream promoter regions of the PtLBD genes. Thirty-five PtLBDs were found to be engaged in either tandem or segmental duplications, and genomic collinearity analysis revealed a stronger alignment between PtLBD genes and eudicots plants compared to their relationship with monocots. GO enrichment and temporal-spatio expression patterns showed that PtLBD7 from subfamily-I and PtLBD20 from subfamily-II, along with other 13 PtLBDs, were involved in plant growth and development biological processes. The multilayered hierarchical gene networks (ML-hGRN) mediated by PtLBD7 and PtLBD20 indicated that PtLBDs were mainly function in poplar growth and stress tolerance through a multifaceted and intricate regulatory machinery. This study lays a solid groundwork for delving deeper into the roles and underlying mechanisms of LBD transcription factors in poplar, specifically those related to plant hormones and stress tolerance.

Genome-wide analysis and expression characteristics of Small Auxin-up RNAs genes in flax (Linum usitatissimum L.)

Plant auxin is crucial in regulating many aspects of plant growth and development. Small Auxin-up RNAs (SAURs) genes act as the main early auxin response genes and are involved in regulating plant growth and development. Flax is a well-known fiber and oil crop; thus, our study provided a systematic bioinformatics analysis of the SAUR family in flax, including basic parameters, gene structure, chromosomal location, phylogenetic analysis, and cis-acting element analysis. Based on genomic information, 86 LusSAUR genes were identified and separated into eight groups. The gene structure analysis revealed that only two LusSAUR genes have introns. The cis-acting elements related to hormones and stress were abundant in the promoter region of LusSAUR members. Based on the gene expression oligo microarray, LusSAUR genes had tissue-specific expression characteristics in eight different tissues. Quantitative real-time PCR analysis indicated that 10 selected LusSAUR genes could be quickly upregulated following treatment with IAA. The 10 genes displayed distinctive expression levels under hormone treatment (MeJA, ABA, SA) and abiotic stress (PEG, NaCl, CdCl2). This study provides a foundation for further investigations for functional analysis of LusSAURs in flax. Furthermore, it will provide useful insights for further research into the molecular mechanism of regulating hormones and environmental signals in flax growth and development.

Effects of dietary Bacillus pumilus on the growth, intestinal health, lipid metabolism, and mTOR signaling pathway of juvenile coho salmon (Oncorhynchus kisutch)

Effects of dietary Bacillus pumilus on the growth, intestinal health, lipid metabolism, and mTOR signaling pathway of juvenile coho salmon (Oncorhynchus kisutch)

North India Cancer Risk: A Detailed Review with Focus on Jammu and Kashmir Demographics.

Cancer is a global medical challenge, and research is at its peak to understand the unique mechanisms of cancer cells. The expanding field of epidemiology, including molecular and environmental studies, helps us better understand the distribution of molecular changes and environmental risk factors in the population. In the present review, we aimed to find out the different genes and environmental factors that are associated with different cancers in the Jammu & Kashmir (J&K) region of the North Indian population. A Systematic approach of literature survey was used to curate research data based on genetic and environmental epidemiology specifying the J&K region. Of 640 articles found initially and screening of 490 records, 97 studies were included for the final review. It was observed that numerous genes that are strongly linked to various cancer types have been discovered as a result of the rising genotyping trend, which has grown in the demography exponentially over the last few decades. The majority of these genes are related to cell cycle regulation, cell growth signaling, and apoptosis regulation. Additionally, high promoter hypermethylation of various genes which were found to be attributed to the presence of distinct dietary patterns. The most important environmental risk attributes were salt tea consumption and dried pickles. In conclusion, the J&K population possesses many common polymorphisms in various genes with a small effect size that makes individuals more prone to different forms of cancers interacting with different environmental factors. What we can't do is, change the gene sequence or molecular changes which are the main changes for determining the susceptibility of any altered condition but what we can do is lower/ limit the exposure to the environmental factors which is a key element playing with the susceptibility's threshold. Therefore, limiting exposure to environmental factors could be a major step in lowering the risk of disease.

Investigating the impact of clinical and genetic factors on the post-surgery prognosis of sinonasal squamous cell carcinoma

Sinonasal squamous cell carcinoma (SNSCC) is an aggressive cancer affecting the nasal and sinus regions, with its progression factors, particularly genetic ones, not yet fully understood. Here, we first conducted a retrospective study with 219 SNSCC patients to identify clinical factors affecting SNSCC prognosis. Additionally, we mined a vast literature dataset to uncover genetic factors associated with SNSCC progression. Based on this data, we constructed SNSCC prognosis pathways and performed a gene set enrichment analysis (GSEA). Clear operative margins were linked to a 73.5–86.3% improvement in overall survival and a 73.5–88.9% lower risk of recurrence. Nasal cavity-originated cases exhibited a 67.6–97.4% decrease in mortality and an 80.7–96.7% lower recurrence rate. Patients at T1-2 staging had a 65.0–80.6% reduced risk of death and recurrence compared to those at T3 stage. Additionally, we identified 53 genes associated with SNSCC, with 14 also implicated in primary tumor site, T stage, and operative margin. These genes, including EGFR, PIK3CA, ERBB2, PTEN, BCL2, BRAF, KRAS, and PRL, form a complex SNSCC-prognosis pathway and were significantly enriched in 42 KEGG pathways and Gene Ontology (GO) terms (FDR-corrected p-value < 0.001), influencing cell growth, apoptosis, and oncogenic signaling pathways. Our study suggests that three clinical parameters (operative margin type, primary tumor site, and T-stage) and 14 genetic factors may influence SNSCC prognosis post-surgery. These findings deepen our understanding of SNSCC and offer potential avenues to enhance its treatment and outcomes.

How might acne and prostate cancer be connected?

Acne and prostate cancer are in part indirectly connected by dietary characteristics that lead to overstimulation of cellular growth signaling. Further, they are directly connected by a proinflammatory phylotype of the acne related bacterium, Cutibacterium acnes, which spreads from acne affected skin to prostate tissue and exists there chronically within a biofilm it secretes, resulting in a local inflammatory and immunosuppressive microenvironment, eventually culminating in prostate cancer initiation and progression. The diet-acne-prostate cancer nexus needs to be explored further and has implications regarding diet, antibiotics, and vaccinations in the prevention and treatment of prostate cancer.

AKT-mediated phosphorylation of TSC2 controls stimulus- and tissue-specific mTORC1 signaling and organ growth.

Mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) integrates diverse intracellular and extracellular growth signals to regulate cell and tissue growth. How the molecular mechanisms regulating mTORC1 signaling established through biochemical and cell biological studies function under physiological states in specific mammalian tissues are unknown. Here, we characterize a genetic mouse model lacking the 5 phosphorylation sites on the tuberous sclerosis complex 2 (TSC2) protein through which the growth factor-stimulated protein kinase AKT can active mTORC1 signaling in cell culture models. These phospho-mutant mice (TSC2-5A) are developmentally normal but exhibit reduced body weight and the weight of specific organs, such as brain and skeletal muscle, associated with cell intrinsic decreases in growth factor-stimulated mTORC1 signaling. The TSC2-5A mouse model demonstrates that TSC2 phosphorylation is a primary mechanism of mTORC1 activation in some, but not all, tissues and provides a genetic tool to facilitate studies on the physiological regulation of mTORC1.

Genome-wide association study of hypersensitivity skin reactions induced by nonionic iodinated contrast media.

In Taiwan, nonionic iodinated contrast media (ICMs) are commonly used but can occasionally cause severe side effects. The infrequency of these adverse events, coupled with the complexities in establishing direct causality, poses significant challenges for genetic research. : To investigate the genetic factors associated with skin reactions mediated by nonionic ICMs on a genome-wide scale. A hospital-based cohort from the China Medical University Hospital biobank was utilized to conduct a comprehensive genome-wide association study (GWAS) using PLINK v1.9. The study incorporated two distinct cohorts: one based on adverse drug reaction (ADR) reports, capturing immediate reactions, and the other based on self-reports, which primarily reflected delayed reactions. Known loci were determined by the GWAS catalog. Fine mapping was conducted by FINEMAP to predict causal variants. Pathway enrichment analysis was performed by clusterProfiler to reveal the biological function of the identified genetic signatures. The ADR-based cohort included 120 cases and 3640 controls. GWAS identified 6 candidate risk loci, namely rs150515068, rs6847491, rs192044153, rs191908641, rs376660317, and rs368821335. The self-report-based cohort, consisting of 275 cases and 8338 controls, revealed 36 additional candidate risk loci. Fine mapping further identified 4 causal variants within each cohort. Pathway analysis showed that immediate HSR-related genes are linked to growth hormone response and signaling, while non-immediate HSR genes are involved in neurotransmission. This study offers new perspectives on the genetic foundation of nonionic ICM-induced skin reactions within the Taiwanese population, suggesting that the genes contributing to immediate and non-immediate HSRs might have different functional roles.

Capsaicin Promotes Apoptosis and Inhibits Cell Migration via the Tumor Necrosis Factor-Alpha (TNFα) and Nuclear Factor Kappa B (NFκB) Signaling Pathway in Oral Cancer Cells.

Background Oral squamous cell carcinoma (OSCC) is a highly prevalent cancer worldwide. Microbial infections, poor oral hygiene, and chronic viral infections such as human papillomavirus (HPV) contribute to its incidence. Capsaicin, known for its presence in chili peppers, has demonstrated potential antiproliferative effects in cancer cells. It operates by inducing programmed cell death, regulating the expression of transcription factors, halting cell cycle progression, and influencing growth signal transduction pathways. These findings suggest capsaicin's promising role as a candidate for further exploration in combating oral cancer. Aim This study intends to identify and evaluate the anticancer properties of capsaicin on oral cancer cells through in vitro investigations. Methodology Using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) technique, the cell viability of oral cancer cells treated with capsaicin was evaluated. Capsaicin was applied to the KB1 cells in a range of concentrations (25-150 µg/mL) over 24 hours. The morphological alterations of the cells were assessed using a phase contrast microscope. Nuclear factor kappa B (NFκB) and tumor necrosis factor-alpha (TNFα) were subjected to quantitative real-time polymerase chain reaction (PCR) gene expression analysis. To investigate nuclear morphological changes, oral cancer cells were stained with acridine orange/ethidium bromide (AO/EtBr). The apoptotic nuclei were visualized using a fluorescent microscope. A scratch wound healing test was performed to check for capsaicin's anti-migratory potential. Result In our investigation of oral cancer cells treated with capsaicin, there was a significant drop in cell viability between the control and treatment groups (p < 0.05). The inhibitory concentration (IC50) was found to be 74.4 μM/mL in oral cancer cells. Following treatment, fewer cells were present, and those that were present shriveled and exhibited cytoplasmic membrane blebbing. Under AO/EtBr staining, treated cells exhibited chromatin condensation and nuclear disintegration. Furthermore, the migration of capsaicin-treated cells was significantly lower than that of control cells. The results of gene expression analysis demonstrated a considerable downregulation of TNFα and NFκB following capsaicin administration. Conclusion The study's findings suggest that capsaicin may have anti-tumor properties in oral cancer cells. More research is desperately needed to fully understand the mechanism underlying capsaicin's anticancer potential and therapeutic applicability.

Involvement of sphingosine 1-phosphate signaling in insulin-like growth factor-II/mannose 6-phosphate receptor trafficking from endosome to the trans-Golgi network

The insulin-like growth factor II/mannose 6-phosphate (IGF-II/M6P) receptor is a multifunctional glycoprotein not only play roles in IGF-II degradation and pro-TGFβ activation but binding to and transport M6P-bearing lysosomal enzymes from the trans-Golgi network (TGN) or the cell surface to lysosomes. At present, information regarding a retrograde transport of IGF-II/M6P receptor from endosomes to the TGN is still limited. We show here that a continuous ligand-dependent activation of sphingosine 1-phosphate receptor type 3 (S1P3R) on the endosomal membranes is required for subsequent recycling back of cargo-unloaded IGF-II/M6P receptors to the TGN. We have further clarified that Gq coupled with S1P3R plays a critical role in the activation of casein kinase 2, which phosphorylates and keeps PACS1 connector protein active for the association with IGF-II/M6P receptors, which enables transport carrier formation with the aid of other adaptor proteins toward the TGN. These findings shed light on the molecular mechanism underlying how continuous activation of the S1P receptor and subsequent downstream Gq signaling regulates the retrograde transport of the empty IGF-II/M6P receptors back to the TGN.

The anticancer effects of Aronia berry extract are mediated by Chk1 and p53 in colorectal cancer

BackgroundAronia berry extracts (ABE) have recently been reported to possess significant anti-cancer effects in various malignancies, including colorectal cancer (CRC), due to their high polyphenolic content. However, the molecular mechanism(s) underlying the anti-cancer effects of ABE in CRC remain unclear, which is important to consider when considering their use as complementary medicine approaches in cancer. MethodsWe performed genome-wide transcriptomic profiling and pathway enrichment analysis to identify specific growth signaling pathways associated with ABE treatment in CRC cells. In addition, a series of systematic and comprehensive cell culture studies were performed to investigate the anti-cancer effects of ABE in SW480 and HCT116 CRC cell lines. Subsequently, these findings were validated in patient-derived 3D organoids (PDOs) models. ResultsTranscriptomic profiling analysis identified p53 signaling as one of the key enriched pathways mediating the anti-cancer activity of ABE. Analysis of public datasets revealed that Chk1, a key regulator of p53, was one of the critical targets of ABE in CRC. Chk1 and p53 activation was shown to be downregulated with ABE treatment, leading to the induction of cell cycle arrest (p = 0.003–0.014) and enhanced DNA damage (p = 0.015–0.026). Furthermore, these findings were validated in PDOs, where the ABE treatment resulted in significantly fewer and smaller PDOs in a concentration-dependent manner (p = 0.045 - <0.001). ConclusionsWe firstly provide evidence for the role of the p53 signaling pathway as a mediator of the anti-cancer activity of ABE, which provides a rationale for its use as a safe and effective integrative medicine approach in CRC.

Integrative transcriptomics and proteomics analysis provide a deep insight into goose astrovirus-host interactions during GAstV infection

Goose astrovirus (GAstV) is a newly discovered astrovirus. GAstV causes gout and death in 4- to -16-day-old goslings. For the past few years, fatal gout, the cardinal clinical symptom of gosling infected with GAstV, has been spreading rapidly in some goose Chinese farms, which caused continuous economic losses to the goose breeding industry in China. Currently, several underlying mechanisms involved in viral replication, inflammatory reaction, virions release, and viral pathogenesis of GAstV remain to be elucidated. In this study, we explored the mechanisms of GAstV-host interactions, the transcriptome and proteome profiles of GAstV-infected LMH cells were sequenced by RNA-seq and data-independent acquisition (DIA) techniques, respectively, and followed using an integrative analysis. Compared with uninfected LMH cells, a total of 322 differentially expressed genes (DEG) (195 up-regulated, 127 down-regulated) and 36 differentially expressed proteins (DEP) (31 up-regulated, 5 down-regulated) were detected. Nine DEGs were randomly selected for further validation by quantitative real-time polymerase chain reaction (qPCR). Through GO and KEGG enrichment analysis, DEG and DEP were significantly enriched in several important cellular signaling pathways, including MAPK, PI3K-Akt, cAMP, chemokine, calcium, phospholipase D, Ras, TNF, IL-17, Rap1, NF-kappa B signaling pathways, indicating that GAstV affects cell growth and immune signaling. This study provided an overview of changes in transcriptome and proteome profiles of GAstV-infected LMH cells, therefore, providing a crucial basis to further explore the mechanisms of GAstV-host interactions.

Adiponectin and Leptin during Pregnancy: A Systematic Review of Their Association with Pregnancy Disorders, Fetal Growth and Placental Function

During pregnancy, the adipokines leptin and adiponectin can affect placental nutrient transport and inflammatory pathways, potentially leading to altered fetal growth and pregnancy complications including gestational diabetes mellitus (GDM) and preeclampsia (PE). The aim of this systematic review is to gather and analyze research on maternal circulating leptin and adiponectin levels and their relationship to adverse pregnancy and birth outcomes. Additionally, it seeks to determine whether these hormones are linked to alterations in placental transporters and cell signaling pathways. PubMed and MEDLINE were systematically searched to include studies published between 2012 and 2022. All primary data studies reporting serum adiponectin and/or leptin, placental mRNA and protein levels of related transporters, and adverse birth outcomes were eligible. The current systematic review encompasses a total of 14 articles. Abnormal serum maternal leptin and adiponectin levels were associated with changes in fetal growth and placental cellular signaling and nutrient transporters. A majority of studies associated elevated maternal leptin and reduced adiponectin with fetal overgrowth, although this relationship was not consistent and may be complicated when other pathologies are present. The effects of maternal leptin and adiponectin on fetal growth may be driven by placental adaptation in nutrient transporters and mitochondria. Future studies should determine if the placental effects of leptin and adiponectin that have been found in models have mechanistic roles in human pregnancy.

Advancing insights into calcium homeostasis and signaling in plant growth and resilience

Advancing insights into calcium homeostasis and signaling in plant growth and resilience

Plant Growth Promoting Rhizobacteria (PGPR) induced protection: A plant immunity perspective.

Plant-environment interactions, particularly biotic stress, are increasingly essential for global food security due to crop losses in the dynamic environment. Therefore, understanding plant responses to biotic stress is vital to mitigate damage. Beneficial microorganisms and their association with plants can reduce the damage associated with plant pathogens. One such group is PGPR (Plant growth-promoting rhizobacteria), which influences plant immunity significantly by interacting with biotic stress factors and plant signalling compounds. This review explores the types, metabolism, and mechanisms of action of PGPR, including their enzyme pathways and the signalling compounds secreted by PGPR that modulate gene and protein expression during plant defence. Furthermore, the review will delve into the crosstalk between PGPR and other plant growth regulators and signalling compounds, elucidating the physiological, biochemical, and molecular insights into PGPR's impact on plants under multiple biotic stresses, including interactions with fungi, bacteria, and viruses. Overall, the review comprehensively adds to our knowledge about PGPR's role in plant immunity and its application for agricultural resilience and food security.

An improved assessment of forest disturbance using a novel approach of combining a Gaussian mixture model with an EM algorithm

Forests have experienced unprecedented decline and mortality beyond their historical range in past decades, which is attributed to disturbances like drought, fire, insects and disease. Traditional disturbance detection methods that typically employ a time series perspective to identify discrete disturbance events within continuous tree growth signals and were mainly designed for gap-scale often fail to identify disturbances across populations. To more accurately identify growth suppression and release clusters based on the perspective of forest population dynamics, here we applied a novel method of detecting forest disturbances using a Gaussian mixture model with an expectation maximisation algorithm (DGE), to fit annual distributions of growth indicators, i.e., tree-ring index. We further compared our novel approach of DGE with five traditional methods based on two sets of real tree-ring data and simulated tree-ring data. The results show an improvement of accuracy (35.5 %–48.1 %), sensitivity (36.6 %–58.1 %), precision (21.2 %–51.5 %) and specificity (11.1 %–20.6 %) for the average of two real radial growth datasets and an improvement of accuracy (7.6 %–13.9 %), sensitivity (70 %), precision (100 %) and specificity (9.1 %–9.7 %) for the simulation radial growth dataset, indicating that our DGE approach performs much better than the traditional methods. This study contributes to an improved strategy and understanding for sustainable forest management in the context of climate warming, demonstrating that our DGE approach can be better applied to global forest disturbance detection under global change.

Targeting Asparagine Metabolism in Well-Differentiated/Dedifferentiated Liposarcoma.

mTORC1 activity is dependent on the presence of micronutrients, including Asparagine (Asn), to promote anabolic cell signaling in many cancers. We hypothesized that targeting Asn metabolism would inhibit tumor growth by reducing mTORC1 activity in well-differentiated (WD)/dedifferentiated (DD) liposarcoma (LPS). Human tumor metabolomic analysis was utilized to compare abundance of Asn in WD vs. DD LPS. Gene set enrichment analysis (GSEA) compared relative expression among metabolic pathways upregulated in DD vs. WD LPS. Proliferation assays were performed for LPS cell lines and organoid models by using the combination treatment of electron transport chain (ETC) inhibitors with Asn-free media. 13C-Glucose-labeling metabolomics evaluated the effects of combination treatment on nucleotide synthesis. Murine xenograft models were used to assess the effects of ETC inhibition combined with PEGylated L-Asparaginase (PEG-Asnase) on tumor growth and mTORC1 signaling. Asn was enriched in DD LPS compared to WD LPS. GSEA indicated that mTORC1 signaling was upregulated in DD LPS. Within available LPS cell lines and organoid models, the combination of ETC inhibition with Asn-free media resulted in reduced cell proliferation. Combination treatment inhibited nucleotide synthesis and promoted cell cycle arrest. In vivo, the combination of ETC inhibition with PEG-Asnase restricted tumor growth. Asn enrichment and mTORC1 upregulation are important factors contributing to WD/DD LPS tumor progression. Effective targeting strategies require limiting access to extracellular Asn and inhibition of de novo synthesis mechanisms. The combination of PEG-Asnase with ETC inhibition is an effective therapy to restrict tumor growth in WD/DD LPS.