bims-glucam 2023-12-17 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2023–12–17
fourteen papers selected by
Sreeparna Banerjee, Middle East Technical University

Glutaminase inhibition as potential cancer therapeutics: current status and future applications.
Glutamine addiction and therapeutic strategies in pancreatic cancer.
Two Faces of Glutaminase GLS2 in Carcinogenesis.
The pan-cancer landscape of glutamate and glutamine metabolism: A comprehensive bioinformatic analysis across 32 solid cancer types.
Targeting glutamine dependence with DRP-104 inhibits proliferation and tumor growth of castration-resistant prostate cancer.
Supraphysiological glutamine as a means of depleting intracellular amino acids to enhance pancreatic cancer chemosensitivity.
The interplay of the circadian clock and metabolic tumorigenesis.
Multivariate modeling of metabolic state vulnerabilities across diverse cancer contexts reveals synthetically lethal associations.
Targeting Metabolic Vulnerabilities to Overcome Prostate Cancer Resistance: Dual Therapy with Apalutamide and Complex I Inhibition.
The amino acid transporter SLC7A11 expression in breast cancer.
Metabolic Profiles of Cancer Stem Cells and Normal Stem Cells and Their Therapeutic Significance.
Glutamine Alleviates I/R-Induced Intestinal Injury and Dysmotility Via the Downregulation of Xanthine Oxidase/Uric Acid Signaling and Lactate Generation in Wistar Rats.
Increased glucose metabolism and impaired glutamate transport in human astrocytes are potential early triggers of abnormal extracellular glutamate accumulation in hiPSC-derived models of Alzheimer's disease.
Charting the transcriptomic landscape of primary and metastatic cancers in relation to their origin and target normal tissues.

J Enzyme Inhib Med Chem. 2024 Dec;39(1): 2290911

Glutaminase inhibition as potential cancer therapeutics: current status and future applications.

Rajath Cyriac, Kwangho Lee.

  Alterations in normal metabolic processes are defining features of cancer. Glutamine, an abundant amino acid in the human blood, plays a critical role in regulating several biosynthetic and bioenergetic pathways that support tumour growth. Glutaminolysis is a metabolic pathway that converts glutamine into various metabolites involved in the tricarboxylic acid (TCA) cycle and generates antioxidants that are vital for tumour cell survival. As glutaminase catalyses the initial step of this metabolic pathway, it is of great significance in cancer metabolism and tumour progression. Inhibition of glutaminase and targeting of glutaminolysis have emerged as promising strategies for cancer therapy. This review explores the role of glutaminases in cancer metabolism and discusses various glutaminase inhibitors developed as potential therapies for tumour regression.

Keywords:  GLS; KEAP1 mutation; anticancer; cancer metabolism; glutaminase

DOI:  https://doi.org/10.1080/14756366.2023.2290911
World J Gastrointest Oncol. 2023 Nov 15. 15(11): 1852-1863

Glutamine addiction and therapeutic strategies in pancreatic cancer.

Lin-Lin Ren, Tao Mao, Pin Meng, Li Zhang, Hong-Yun Wei, Zi-Bin Tian.

  Pancreatic cancer remains one of the most lethal diseases worldwide owing to its late diagnosis, early metastasis, and poor prognosis. Because current therapeutic options are limited, there is an urgent need to investigate novel targeted treatment strategies. Pancreatic cancer faces significant metabolic challenges, principally hypoxia and nutrient deprivation, due to specific microenvironmental constraints, including an extensive desmoplastic stromal reaction. Pancreatic cancer cells have been shown to rewire their metabolism and energy production networks to support rapid survival and proliferation. Increased glucose uptake and glycolytic pathway activity during this process have been extensively described. However, growing evidence suggests that pancreatic cancer cells are glutamine addicted. As a nitrogen source, glutamine directly (or indirectly via glutamate conversion) contributes to many anabolic processes in pancreatic cancer, including amino acids, nucleobases, and hexosamine biosynthesis. It also plays an important role in redox homeostasis, and when converted to α-ketoglutarate, glutamine serves as an energy and anaplerotic carbon source, replenishing the tricarboxylic acid cycle intermediates. The present study aims to provide a comprehensive overview of glutamine metabolic reprogramming in pancreatic cancer, focusing on potential therapeutic approaches targeting glutamine metabolism in pancreatic cancer.

Keywords:  Cancer treatment; Glutamine metabolism; Pancreatic cancer; Therapeutic strategies

DOI:  https://doi.org/10.4251/wjgo.v15.i11.1852
Cancers (Basel). 2023 Nov 24. pii: 5566. [Epub ahead of print]15(23):

Two Faces of Glutaminase GLS2 in Carcinogenesis.

Joanna Buczkowska, Monika Szeliga.

  In rapidly proliferating cancer cells, glutamine is a major source of energy and building blocks. Increased glutamine uptake and enhanced glutaminolysis are key metabolic features of many cancers. Glutamine is metabolized by glutaminase (GA), which is encoded by two genes: GLS and GLS2. In contrast to isoforms arising from the GLS gene, which clearly act as oncoproteins, the role of GLS2 products in tumorigenesis is far from well understood. While in some cancer types GLS2 is overexpressed and drives cancer development, in some other types it is downregulated and behaves as a tumor suppressor gene. In this review, we describe the essential functions and regulatory mechanisms of human GLS2 and the cellular compartments in which GLS2 has been localized. Furthermore, we present the context-dependent oncogenic and tumor-suppressor properties of GLS2, and delve into the mechanisms underlying these phenomena.

Keywords:  apoptosis; epithelial-mesenchymal transition; ferroptosis; glutaminase GLS2; glutamine metabolism; oxidative stress; tumor promoter; tumor suppressor

DOI:  https://doi.org/10.3390/cancers15235566
Biochim Biophys Acta Mol Basis Dis. 2023 Dec 06. pii: S0925-4439(23)00348-4. [Epub ahead of print]1870(2): 166982

The pan-cancer landscape of glutamate and glutamine metabolism: A comprehensive bioinformatic analysis across 32 solid cancer types.

Wenhua Xue, Kai Wu, Xiaona Guo, Chengxin Chen, Tao Huang, Lifeng Li, Bin Liu, Hao Chang, Jie Zhao.

  Glutamine metabolism is a hallmark of cancer metabolism, which matters in the progression of the tumor. This synthetic study conducted a large-scale systematic analysis at the pan-cancer level on the glutamate and glutamine metabolism (GGM) across 32 solid tumors from the TCGA database. The glutamine metabolism activity was quantified through a scoring system. This study revealed that the GGM score in tumor tissues was up-regulated in 13 cancer types (BCLA, BRCA, COAD, KICH, KIRP, LUAD, LUSC, PAAD, PRAD, READ, STAD, THYM, UCEC) and down-regulated in 4 cancer types (CHOL, GBM, LIHC, THCA), exhibiting tissue specificity. The mRNA expression levels of glutamine metabolism-related genes were relatively high, and GLUL exhibited the highest expression level. The expression levels were up-regulated with copy number amplification. ALDH18A1, PYCR1, and PYCR2 show a significant upregulation in protein levels in cancer tissues compared to normal tissues, making them potential pan-cancer therapeutic targets. For the TME related to glutamine metabolism, the GGM score exhibited significant immune and stromal environment inhibitory effects in all involved tumors. Up-regulated GGM score indicated the widespread promotion of drug resistance at the pan-cancer level. GGM score and glutamine metabolism-related genes signature tended to be risk factors for the overall survival of cancer patients.

Keywords:  Drug sensitivity; Genetic alternations; Glutamate and glutamine metabolism; Molecular subtypes; Prognosis; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.bbadis.2023.166982
Prostate. 2023 Dec 12.

Targeting glutamine dependence with DRP-104 inhibits proliferation and tumor growth of castration-resistant prostate cancer.

David Moon, J Spencer Hauck, Xue Jiang, Holly Quang, Lingfan Xu, Fan Zhang, Xia Gao, Robert Wild, Jeffrey I Everitt, Everardo Macias, Yiping He, Jiaoti Huang.

   BACKGROUND: Prostate cancer (PCa) continues to be one of the leading causes of cancer deaths in men. While androgen deprivation therapy is initially effective, castration-resistant PCa (CRPC) often recurs and has limited treatment options. Our previous study identified glutamine metabolism to be critical for CRPC growth. The glutamine antagonist 6-diazo-5-oxo-l-norleucine (DON) blocks both carbon and nitrogen pathways but has dose-limiting toxicity. The prodrug DRP-104 is expected to be preferentially converted to DON in tumor cells to inhibit glutamine utilization with minimal toxicity. However, CRPC cells' susceptibility to DRP-104 remains unclear.
METHODS: Human PCa cell lines (LNCaP, LAPC4, C4-2/MDVR, PC-3, 22RV1, NCI-H660) were treated with DRP-104, and effects on proliferation and cell death were assessed. Unbiased metabolic profiling and isotope tracing evaluated the effects of DRP-104 on glutamine pathways. Efficacy of DRP-104 in vivo was evaluated in a mouse xenograft model of neuroendocrine PCa, NCI-H660.
RESULTS: DRP-104 inhibited proliferation and induced apoptosis in CRPC cell lines. Metabolite profiling showed decreases in the tricarboxylic acid cycle and nucleotide synthesis metabolites. Glutamine isotope tracing confirmed the blockade of both carbon pathway and nitrogen pathways. DRP-104 treated CRPC cells were rescued by the addition of nucleosides. DRP-104 inhibited neuroendocrine PCa xenograft growth without detectable toxicity.
CONCLUSIONS: The prodrug DRP-104 blocks glutamine carbon and nitrogen utilization, thereby inhibiting CRPC growth and inducing apoptosis. Targeting glutamine metabolism pathways with DRP-104 represents a promising therapeutic strategy for CRPC.

Keywords:  DRP-104; cancer metabolism; castration-resistant

DOI:  https://doi.org/10.1002/pros.24654
Res Sq. 2023 Nov 30. pii: rs.3.rs-3647514. [Epub ahead of print]

Supraphysiological glutamine as a means of depleting intracellular amino acids to enhance pancreatic cancer chemosensitivity.

Neil Bhowmick, Hayato Muranaka, Sandrine Billet, Carlos Cruz-Hernández, Johanna Ten Hoeve, Gabrielle Gonzales, Omer Elmadbouh, Le Zhang, Bethany Smith, Mourad Tighiouart, Sungyong You, Mouad Edderkaoui, Andrew Hendifar, Stephen Pandol, Jun Gong.

Limited efficacy of systemic therapy for pancreatic ductal adenocarcinoma (PDAC) patients contributes to high mortality. Cancer cells develop strategies to secure nutrients in nutrient-deprived conditions and chemotherapy treatment. Despite the dependency of PDAC on glutamine (Gln) for growth and survival, strategies designed to suppress Gln metabolism have limited effects. Here, we demonstrated that supraphysiological concentrations of glutamine (SPG) could produce paradoxical responses leading to tumor growth inhibition alone and in combination with chemotherapy. Integrated metabolic and transcriptomic analysis revealed that the growth inhibitory effect of SPG was the result of a decrease in intracellular amino acid and nucleotide pools. Mechanistically, disruption of the sodium gradient, plasma membrane depolarization, and competitive inhibition of amino acid transport mediated amino acid deprivation. Among standard chemotherapies given to PDAC patients, gemcitabine treatment resulted in a significant enrichment of amino acid and nucleoside pools, exposing a metabolic vulnerability to SPG-induced metabolic alterations. Further analysis highlighted a superior anticancer effect of D-glutamine, a non-metabolizable enantiomer of the L-glutamine, by suppressing both amino acid uptake and glutaminolysis, in gemcitabine-treated preclinical models with no apparent toxicity. Our study suggests supraphysiological glutamine could be a means of inhibiting amino acid uptake and nucleotide biosynthesis, potentiating gemcitabine sensitivity in PDAC.

DOI: https://doi.org/10.21203/rs.3.rs-3647514/v1
Trends Cell Biol. 2023 Dec 06. pii: S0962-8924(23)00237-4. [Epub ahead of print]

The interplay of the circadian clock and metabolic tumorigenesis.

Zheng Wang, Leina Ma, Ying Meng, Jing Fang, Daqian Xu, Zhimin Lu.

  The circadian clock and cell metabolism are both dysregulated in cancer cells through intrinsic cell-autonomous mechanisms and external influences from the tumor microenvironment. The intricate interplay between the circadian clock and cancer cell metabolism exerts control over various metabolic processes, including aerobic glycolysis, de novo nucleotide synthesis, glutamine and protein metabolism, lipid metabolism, mitochondrial metabolism, and redox homeostasis in cancer cells. Importantly, oncogenic signaling can confer a moonlighting function on core clock genes, effectively reshaping cellular metabolism to fuel cancer cell proliferation and drive tumor growth. These interwoven regulatory mechanisms constitute a distinctive feature of cancer cell metabolism.

Keywords:  cancer metabolism; dysregulated circadian clock; moonlighting function

DOI:  https://doi.org/10.1016/j.tcb.2023.11.004
bioRxiv. 2023 Nov 29. pii: 2023.11.28.569098. [Epub ahead of print]

Multivariate modeling of metabolic state vulnerabilities across diverse cancer contexts reveals synthetically lethal associations.

Cara Abecunas, Mohammad Fallahi-Sichani.

Targeting the distinct metabolic needs of tumor cells has recently emerged as a promising strategy for cancer therapy. The heterogeneous, context-dependent nature of cancer cell metabolism, however, poses challenges in identifying effective therapeutic interventions. Here, we utilize various unsupervised and supervised multivariate modeling approaches to systematically pinpoint recurrent metabolic states within hundreds of cancer cell lines, elucidate their association with tissue lineage and growth environments, and uncover vulnerabilities linked to their metabolic states across diverse genetic and tissue contexts. We validate key findings using data from an independent set of cell lines, pharmacological screens, and via single-cell analysis of patient-derived tumors. Our analysis uncovers new synthetically lethal associations between the tumor metabolic state (e.g., oxidative phosphorylation), driver mutations (e.g., loss of tumor suppressor PTEN), and actionable biological targets (e.g., mitochondrial electron transport chain). Investigating these relationships could inform the development of more precise and context-specific, metabolism-targeted cancer therapies.

DOI: https://doi.org/10.1101/2023.11.28.569098
Cancers (Basel). 2023 Nov 28. pii: 5612. [Epub ahead of print]15(23):

Targeting Metabolic Vulnerabilities to Overcome Prostate Cancer Resistance: Dual Therapy with Apalutamide and Complex I Inhibition.

Valentin Baumgartner, Dominik Schaer, Daniel Eberli, Souzan Salemi.

  Prostate cancer (PCa) often becomes drug-treatment-resistant, posing a significant challenge to effective management. Although initial treatment with androgen deprivation therapy can control advanced PCa, subsequent resistance mechanisms allow tumor cells to continue growing, necessitating alternative approaches. This study delves into the specific metabolic dependencies of different PCa subtypes and explores the potential synergistic effects of combining androgen receptor (AR) inhibition (ARN with mitochondrial complex I inhibition (IACS)). We examined the metabolic behaviors of normal prostate epithelial cells (PNT1A), androgen-sensitive cells (LNCaP and C4-2), and androgen-independent cells (PC-3) when treated with ARN, IACS, or a combination. The results uncovered distinct mitochondrial activities across PCa subtypes, with androgen-dependent cells exhibiting heightened oxidative phosphorylation (OXPHOS). The combination of ARN and IACS significantly curbed cell proliferation in multiple PCa cell lines. Cellular bioenergetics analysis revealed that IACS reduced OXPHOS, while ARN hindered glycolysis in certain PCa cells. Additionally, galactose supplementation disrupted compensatory glycolytic mechanisms induced by metabolic reprogramming. Notably, glucose-deprived conditions heightened the sensitivity of PCa cells to mitochondrial inhibition, especially in the resistant PC-3 cells. Overall, this study illuminates the intricate interplay between AR signaling, metabolic adaptations, and treatment resistance in PCa. The findings offer valuable insights into subtype-specific metabolic profiles and propose a promising strategy to target PCa cells by exploiting their metabolic vulnerabilities.

Keywords:  IACS-010759; apalutamide; metabolism; mitochondria; prostate cancer

DOI:  https://doi.org/10.3390/cancers15235612
Cancer Biol Ther. 2024 Dec 31. 25(1): 2291855

The amino acid transporter SLC7A11 expression in breast cancer.

Preyanka Nath, Lutfi H Alfarsi, Rokaya El-Ansari, Brendah K Masisi, Busra Erkan, Ali Fakroun, Ian O Ellis, Emad A Rakha, Andrew R Green.

  Breast cancer (BC), characterized by its diverse molecular profiles and clinical outcomes, presents a significant challenge in the development of effective therapeutic strategies. Metabolic reprogramming, a defining characteristic of cancer, has emerged as a promising target for novel therapies. SLC7A11, an amino acid transporter that facilitates cysteine uptake in exchange for glutamate, plays a crucial role in sustaining the altered metabolism of cancer cells. This study delves into the comprehensive analysis of SLC7A11 at the genomic, transcriptomic, and protein levels in extensive BC datasets to elucidate its potential role in different BC subtypes. SLC7A11 gene copy number and mRNA expression were evaluated using the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) cohort (n = 1,980) and Breast Cancer Gene Expression Miner (n = 4,712). SLC7A11 protein was assessed using immunohistochemistry in a large BC cohort (n = 1,981). Additionally, The Cancer Genome Atlas (TCGA) dataset was used to explore SLC7A11 DNA methylation patterns using MethSurv (n = 782) and association of SLC7A11 mRNA expression with immune infiltrates using TIMER (n = 1,100). High SLC7A11 mRNA and SLC7A11 protein expression were significantly associated with high tumor grade (p ≤ .02), indicating a potential role in cancer progression. Interestingly, SLC7A11 copy number gain was observed in HER2+ tumors (p = .01), suggesting a subtype-specific association. In contrast, SLC7A11 mRNA expression was higher in the basal-like/triple-negative (TN; p < .001) and luminal B tumors (p = .02), highlighting its differential expression across BC subtypes. Notably, high SLC7A11 protein expression was predominantly observed in Estrogen Receptor (ER)-negative and Triple Negative (TN) BC, suggesting a role in these aggressive subtypes. Further analysis revealed that SLC7A11 was positively correlated with other amino acid transporters and enzymes associated with glutamine metabolism, implying a coordinated role in metabolic regulation. Additionally, SLC7A11 gene expression was positively associated with neutrophil and macrophage infiltration, suggesting a potential link between SLC7A11 and tumor immunity. Our findings suggest that SLC7A11 plays a significant role in BC metabolism, demonstrating differential expression across subtypes and associations with poor patient outcomes. Further functional studies are warranted to elucidate the precise mechanisms by which SLC7A11 contributes to BC progression and to explore its potential as a therapeutic target.

Keywords:  Breast cancer; IHC; SLC7A11 expression; amino acid transporters; metabolism; prognostic factor; subtypes

DOI:  https://doi.org/10.1080/15384047.2023.2291855
Cells. 2023 Nov 22. pii: 2686. [Epub ahead of print]12(23):

Metabolic Profiles of Cancer Stem Cells and Normal Stem Cells and Their Therapeutic Significance.

Ioannis Stouras, Maria Vasileiou, Panagiotis F Kanatas, Eleni Tziona, Christina Tsianava, Stamatis Theocharis.

  Cancer stem cells (CSCs) are a rare cancer cell population, responsible for the facilitation, progression, and resistance of tumors to therapeutic interventions. This subset of cancer cells with stemness and tumorigenic properties is organized in niches within the tumor microenvironment (TME) and presents altered regulation in a variety of metabolic pathways, including glycolysis, oxidative phosphorylation (OXPHOS), as well as lipid, amino acid, and iron metabolism. CSCs exhibit similarities as well as differences when comparedto normal stem cells, but also possess the ability of metabolic plasticity. In this review, we summarize the metabolic characteristics of normal, non-cancerous stem cells and CSCs. We also highlight the significance and implications of interventions targeting CSC metabolism to potentially achieve more robust clinical responses in the future.

Keywords:  amino acid metabolism; cancerstem cells; glycolysis; lipid metabolism; metabolism; oxidative phosphorylation; stem cells

DOI:  https://doi.org/10.3390/cells12232686
J Surg Res. 2023 Dec 08. pii: S0022-4804(23)00612-1. [Epub ahead of print]295 431-441

Glutamine Alleviates I/R-Induced Intestinal Injury and Dysmotility Via the Downregulation of Xanthine Oxidase/Uric Acid Signaling and Lactate Generation in Wistar Rats.

Roland Eghoghosoa Akhigbe, Bayo-Olugbami Adedamola Aminat, Tunmise Maryanne Akhigbe, Moses Agbomhere Hamed.

   INTRODUCTION: Disruption of intestinal histoarchitecture and intestinal dysmotility is critical to intestinal ischemia/reperfusion (IR) injury and xanthine oxidase (XO)/uric acid (UA) signaling and increased lactate generation have been reported to play a role. More so, glutamine treatment has been demonstrated to inhibit XO/UA signaling. However, the role of glutamine in intestinal IR injury-induced intestinal dysmotility and the associated mechanisms of action are unclear. Therefore, this study was to investigate the mechanisms underlying the role of glutamine in intestinal IR injury.
METHODS: Forty male Wistar rats were acclimatized for two weeks and then randomized into four groups. The sham-operated, glutamine-treated, intestinal IR, and IR + glutamine groups.
RESULTS: Glutamine therapy attenuated the IR-induced increase in intestinal weight, disruption of intestinal histoarchitecture, and intestinal dysmotility. In addition, glutamine ameliorated IR-induced intestinal oxidative stress (increased malondialdehyde, reduced glutathione and superoxide dismutase, catalase, glutathione peroxidase, glutathione-S-transferase, and glucose-6-phosphate dehydrogenase activities), inflammation (increased TNF-α and IL-1β), and apoptosis (increased caspase three activity). These events were accompanied by glutamine alleviation of IR-induced upregulation of intestinal nuclear factor kappa B, XO/UA, and lactate generation.
CONCLUSIONS: In conclusion, XO/UA signaling and lactate levels are key factors in IR-induced intestinal injury and dysmotility, and glutamine-mediated XO/UA/lactate modulation may attenuate IR-induced intestinal injury and dysmotility.

Keywords:  Apoptosis; Caspase; Glutamine; Gut microbiota; Ischemia/reperfusion; Oxidative stress

DOI:  https://doi.org/10.1016/j.jss.2023.11.041
J Neurochem. 2023 Dec 08.

Increased glucose metabolism and impaired glutamate transport in human astrocytes are potential early triggers of abnormal extracellular glutamate accumulation in hiPSC-derived models of Alzheimer's disease.

Claudia Salcedo, Victoria Pozo Garcia, Bernat García-Adán, Aishat O Ameen, Georgi Gegelashvili, Helle S Waagepetersen, Kristine K Freude, Blanca I Aldana.

  Glutamate recycling between neurons and astrocytes is essential to maintain neurotransmitter homeostasis. Disturbances in glutamate homeostasis, resulting in excitotoxicity and neuronal death, have been described as a potential mechanism in Alzheimer's disease (AD) pathophysiology. However, glutamate neurotransmitter metabolism in different human brain cells, particularly astrocytes, has been poorly investigated at the early stages of AD. We sought to investigate glucose and glutamate metabolism in AD by employing human induced pluripotent stem cell (hiPSC)-derived astrocytes and neurons carrying mutations in the amyloid precursor protein (APP) or presenilin-1 (PSEN-1) gene as found in familial types of AD (fAD). Methods such as live-cell bioenergetics and metabolic mapping using [13 C]-enriched substrates were used to examine metabolism in the early stages of AD. Our results revealed greater glycolysis and glucose oxidative metabolism in astrocytes and neurons with APP or PSEN-1 mutations, accompanied by an elevated glutamate synthesis compared to control WT cells. Astrocytes with APP or PSEN-1 mutations exhibited reduced expression of the excitatory amino acid transporter 2 (EAAT2), and glutamine uptake increased in mutated neurons, with enhanced glutamate release specifically in neurons with a PSEN-1 mutation. These results demonstrate a hypermetabolic phenotype in astrocytes with fAD mutations possibly linked to toxic glutamate accumulation. Our findings further identify metabolic imbalances that may occur in the early phases of AD pathophysiology.

Keywords:  APP; PSEN-1; energy metabolism; excitotoxicity; hiPSC astrocytes; hiPSC neurons

DOI:  https://doi.org/10.1111/jnc.16014
bioRxiv. 2023 Nov 02. pii: 2023.10.30.564810. [Epub ahead of print]

Charting the transcriptomic landscape of primary and metastatic cancers in relation to their origin and target normal tissues.

Neel Sanghvi, Camilo Calvo-Alcañiz, Padma S Rajagopal, Stefano Scalera, Valeria Canu, Sanju Sinha, Fiorella Schischlik, Kun Wang, Sanna Madan, Eldad Shulman, Antonios Papanicolau-Sengos, Giovanni Blandino, Eytan Ruppin, Nishanth Ulhas Nair.

Metastasis is a leading cause of cancer-related deaths, yet understanding how metastatic tumors adapt from their origin to target tissues is challenging. To address this, we assessed whether primary and metastatic tumors resemble their tissue of origin or target tissue in terms of gene expression. We analyzed gene expression profiles from various cancer types, including single-cell and bulk RNA-seq data, in both paired and unpaired primary and metastatic patient cohorts. We quantified the transcriptomic distances between tumor samples and their normal tissues, revealing that primary tumors are more similar to their tissue of origin, while metastases shift towards the target tissue. Pathway-level analysis highlighted critical transcriptomic changes during metastasis. Notably, primary cancers exhibited higher activity in cancer hallmarks, including Activating Invasion and Metastasis , compared to metastatic cancers. This comprehensive landscape analysis provides insight into how cancer tumors adapt to their metastatic environments, providing a transcriptome-wide view of the processes involved.

DOI: https://doi.org/10.1101/2023.10.30.564810