A bladder cancer patient-derived xenograft displays aggressive growth dynamics in vivo and in organoid culture

Cai, Elise Y.; García, José Manuel Pérez; Liu, Yuzhen; Vakar-López, Funda; Arora, Sonali; Nguyen, Holly M.; Lakely, Bryce; Brown, Lisha G.; Wong, Alicia Yoke Wei; Montgomery, Bruce; Lee, John K.; Corey, Eva; Wright, Jonathan L.; Hsieh, Andrew C.; Lam, Hung‐Ming

doi:10.1038/s41598-021-83662-7

Cited by 13 publications

(6 citation statements)

References 44 publications

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“…This finding demonstrates the heterogeneity of eIF4E S209 phosphorylation across models of bladder cancer. We subsequently created organoid models from 1 low eIF4E phosphorylation model (CoCaB1) ( 35 ) and 2 high eIF4E phosphorylation models (CoCaB14.1 and TM01029), which recapitulated the in vivo models ( Supplemental Figure 5 ). These low-passage organoid lines were treated with increasing concentrations of eFT508 (0.01–10 μM), validated for target inhibition ( Figure 3C ), and measured for cell viability.…”

Section: Resultsmentioning

confidence: 99%

mRNA translation is a therapeutic vulnerability necessary for bladder epithelial transformation

Jana¹,

Deo²,

Hough³

et al. 2021

JCI Insight

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Using genetically engineered mouse models we demonstrate that protein synthesis is essential for efficient urothelial cancer formation and growth but dispensable for bladder homeostasis.Through a candidate gene analysis for translation regulators implicated in this dependency, we discovered that phosphorylation of the translation initiation factor eIF4E at serine 209 is increased in both murine and human bladder cancer which corresponds with an increase in de novo protein synthesis. Employing an eIF4E serine 209 to alanine knock-in mutant mouse model we show that this single post-translational modification is critical for bladder cancer initiation and progression despite having no impact on normal bladder tissue maintenance. Using murine and human models of advanced bladder cancer, we demonstrate that only tumors with high levels of eIF4E phosphorylation are therapeutically vulnerable to eFT508, the first clinical grade inhibitor of MNK1 and MNK2, the upstream kinases of eIF4E. Together, our results show that phospho-eIF4E plays an important role in bladder cancer pathogenesis and targeting its upstream kinases could be an effective therapeutic option for bladder cancer patients with high levels of eIF4E phosphorylation.

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Section: Resultsmentioning

confidence: 99%

mRNA translation is a therapeutic vulnerability necessary for bladder epithelial transformation

Jana¹,

Deo²,

Hough³

et al. 2021

JCI Insight

Self Cite

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“…Lee et al and Chen et al used an RNA sequencing approach to distinguish normal/tumor pairs in patients with urothelial cancer (GSE159824 and GSE133624) [ 122 , 123 ]. Many scientists have generated their data from patient-derived xenografts (PDXs) and organoids (GSE155007 and GSE134292) [ 124 ]. Such research also includes GSE77952 [ 125 ], GSE125286, GSE111933 [ 126 ], GSE68020, GSE129441 [ 127 ], and GSE103990 [ 128 ].…”

Section: Omics Datasets Available In Ucmentioning

confidence: 99%

Current Development and Application of Anaerobic Glycolytic Enzymes in Urothelial Cancer

Yang

Chuang

Kuo

et al. 2021

IJMS

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Urothelial cancer is a malignant tumor with metastatic ability and high mortality. Malignant tumors of the urinary system include upper tract urothelial cancer and bladder cancer. In addition to typical genetic alterations and epigenetic modifications, metabolism-related events also occur in urothelial cancer. This metabolic reprogramming includes aberrant expression levels of genes, metabolites, and associated networks and pathways. In this review, we summarize the dysfunctions of glycolytic enzymes in urothelial cancer and discuss the relevant phenotype and signal transduction. Moreover, we describe potential prognostic factors and risks to the survival of clinical cancer patients. More importantly, based on several available databases, we explore relationships between glycolytic enzymes and genetic changes or drug responses in urothelial cancer cells. Current advances in glycolysis-based inhibitors and their combinations are also discussed. Combining all of the evidence, we indicate their potential value for further research in basic science and clinical applications.

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“…Patient-derived xenografts (PDXs) are established by directly transplanting tumor tissues from patients into immunodeficient mice, and are the most accurate in vivo model for drug screening [ 7 ]. However, the establishment of PDXs is expensive and time-consuming, which severely limits their clinical applications [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

Lactate promotes the growth of patient-derived organoids from hepatopancreatobiliary cancers via ENO1/HIF1α pathway and does not affect their drug sensitivities

Wang

et al. 2022

Cell Death Discov.

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The long culture duration of patient-derived organoids (PDOs) have severely limited their clinical applications. The aim of this study was to determine the effect of lactate supplementation on the growth, genetic profiles and drug sensitivities of PDOs from hepatopancreatobiliary tumors. LM3, Huh7, Panc02, and RBE cell lines were cultured as organoids in the presence or absence of lactate, and total protein was extracted to measure the expression of α-enolase (ENO1), hypoxia-inducible factor-1α (HIF1α), AKT, and PI3 kinase (PI3K). Thirteen hepatopancreatobiliary tumor specimens were collected during surgical resection and cultured as PDOs with or without l-lactate. Hematoxylin and eosin (H&E) staining and immunohistochemical staining were performed on the original tissues and PDOs to compare their pathological structures, and their genetic profiles were analyzed by whole-exome sequencing (WES). The sensitivity of the PDOs to gemcitabine, 5-fluorouracil, cisplatin, paclitaxel, ivosidenib, infigratinib, and lenvatinib were evaluated in terms of cell viability. Peripheral blood mononuclear cells (PBMCs) were isolated and co-cultured with PDOs to test the sensitivity of PDOs to tislelizumab. The addition of 20 mM lactate significantly promoted the growth of LM3 and Huh 7 organoids by 217% and 36%, respectively, compared to the control group, and the inhibition of lactate transporter decreased their growth. The HIF1α/ENO1/AKT/PI3K pathway was also activated by lactate. The inhibition of enolase also partly decreased the growth of organoids treated with lactate. Furthermore, 20 mM lactate increased the viability of 9 PDOs from 135% to 317% without affecting their pathological features. The genetic similarity, in terms of single nucleotide variations, insertions, and deletions, between original tissues and lactate-treated PDOs ranged from 83.2% to 94.1%, and that between the untreated and lactate-treated PDOs was at least 93.2%. Furthermore, the addition of lactate did not significantly change the dose–response curves of the PDOs to chemotherapeutic drugs, targeted drugs, and immune checkpoint inhibitor, especially for the drugs to which the cells were sensitive. Thus, lactate can be added to the culture medium of PDOs to promote their growth without altering their genetic profiles and drug sensitivities.

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A bladder cancer patient-derived xenograft displays aggressive growth dynamics in vivo and in organoid culture

Cited by 13 publications

References 44 publications

mRNA translation is a therapeutic vulnerability necessary for bladder epithelial transformation

mRNA translation is a therapeutic vulnerability necessary for bladder epithelial transformation

Current Development and Application of Anaerobic Glycolytic Enzymes in Urothelial Cancer

Lactate promotes the growth of patient-derived organoids from hepatopancreatobiliary cancers via ENO1/HIF1α pathway and does not affect their drug sensitivities

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