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1.
JCI Insight ; 9(1)2024 Jan 09.
Article in English | MEDLINE | ID: mdl-38051586

ABSTRACT

The use of patient-derived organoids (PDOs) to characterize therapeutic sensitivity and resistance is a promising precision medicine approach, and its potential to inform clinical decisions is now being tested in several large multiinstitutional clinical trials. PDOs are cultivated in the extracellular matrix from basement membrane extracts (BMEs) that are most commonly acquired commercially. Each clinical site utilizes distinct BME lots and may be restricted due to the availability of commercial BME sources. However, the effect of different sources of BMEs on organoid drug response is unknown. Here, we tested the effect of BME source on proliferation, drug response, and gene expression in mouse and human pancreatic ductal adenocarcinoma (PDA) organoids. Both human and mouse organoids displayed increased proliferation in Matrigel compared with Cultrex and UltiMatrix. However, we observed no substantial effect on drug response when organoids were cultured in Matrigel, Cultrex, or UltiMatrix. We also did not observe major shifts in gene expression across the different BME sources, and PDOs maintained their classical or basal-like designation. Overall, we found that the BME source (Matrigel, Cultrex, UltiMatrix) does not shift PDO dose-response curves or drug testing results, indicating that PDO pharmacotyping is a robust approach for precision medicine.


Subject(s)
Carcinoma, Pancreatic Ductal , Pancreatic Neoplasms , Humans , Animals , Mice , Precision Medicine , Pancreatic Neoplasms/drug therapy , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/metabolism , Carcinoma, Pancreatic Ductal/drug therapy , Carcinoma, Pancreatic Ductal/genetics , Carcinoma, Pancreatic Ductal/metabolism , Extracellular Matrix , Organoids/metabolism
2.
Int J Oncol ; 63(5)2023 Nov.
Article in English | MEDLINE | ID: mdl-37654190

ABSTRACT

Glioblastoma (GBM) is the most common and malignant primary brain tumor affecting adults and remains incurable. The mitochondrial coiled­coil­helix­coiled­coil­helix domain­containing protein 2 (CHCHD2) has been demonstrated to mediate mitochondrial respiration, nuclear gene expression and cell migration; however, evidence of this in GBM is lacking. In the present study, it was hypothesized that CHCHD2 may play a functional role in U87 GBM cells expressing the constitutively active epidermal growth factor receptor variant III (EGFRvIII). The amplification of the CHCHD2 gene was found to be associated with a decreased patient overall and progression­free survival. The CHCHD2 mRNA levels were increased in high­vs. low­grade glioma, IDH­wt GBMs, and in tumor vs. non­tumor tissue. Additionally, CHCHD2 protein expression was greatest in invasive, EGFRvIII­expressing patient­derived samples. The CRISPR­Cas9­mediated knockout of CHCHD2 in EGFRvIII­expressing U87 cells resulted in an altered mitochondrial respiration and glutathione status, in decreased cell growth and invasion under both normoxic and hypoxic conditions, and in an enhanced sensitivity to cytotoxic agents. CHCHD2 was distributed in both the mitochondria and nuclei of U87 and U87vIII cells, and the U87vIII cells exhibited a greater nuclear expression of CHCHD2 compared to isogenic U87 cells. Incubation under hypoxic conditions, serum starvation and the reductive unfolding of CHCHD2 induced the nuclear accumulation of CHCHD2 in both cell lines. Collectively, the findings of the present study indicate that CHCHD2 mediates a variety of GBM characteristics, and highlights mitonuclear retrograde signaling as a pathway of interest in GBM cell biology.


Subject(s)
Brain Neoplasms , Glioblastoma , Adult , Humans , Glioblastoma/pathology , ErbB Receptors/genetics , ErbB Receptors/metabolism , Drug Resistance, Neoplasm , Cell Line, Tumor , Cell Proliferation/genetics , Brain Neoplasms/pathology , Hypoxia , Mitochondria/metabolism , DNA-Binding Proteins/genetics , Transcription Factors
3.
Nat Commun ; 14(1): 5195, 2023 09 06.
Article in English | MEDLINE | ID: mdl-37673892

ABSTRACT

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy in need of new therapeutic options. Using unbiased analyses of super-enhancers (SEs) as sentinels of core genes involved in cell-specific function, here we uncover a druggable SE-mediated RNA-binding protein (RBP) cascade that supports PDAC growth through enhanced mRNA translation. This cascade is driven by a SE associated with the RBP heterogeneous nuclear ribonucleoprotein F, which stabilizes protein arginine methyltransferase 1 (PRMT1) to, in turn, control the translational mediator ubiquitin-associated protein 2-like. All three of these genes and the regulatory SE are essential for PDAC growth and coordinately regulated by the Myc oncogene. In line with this, modulation of the RBP network by PRMT1 inhibition reveals a unique vulnerability in Myc-high PDAC patient organoids and markedly reduces tumor growth in male mice. Our study highlights a functional link between epigenetic regulation and mRNA translation and identifies components that comprise unexpected therapeutic targets for PDAC.


Subject(s)
Carcinoma, Pancreatic Ductal , Pancreatic Neoplasms , Male , Animals , Mice , RNA , Epigenesis, Genetic , Regulatory Sequences, Nucleic Acid , Pancreatic Neoplasms/genetics , Carcinoma, Pancreatic Ductal/genetics , Methyltransferases , RNA-Binding Proteins/genetics
4.
bioRxiv ; 2023 May 09.
Article in English | MEDLINE | ID: mdl-36747742

ABSTRACT

The use of patient-derived organoids (PDOs) to characterize therapeutic sensitivity and resistance (pharmacotyping) is a promising precision medicine approach. The potential of this approach to inform clinical decisions is now being tested in several large multi-institutional clinical trials. PDOs are cultivated in extracellular matrix from basement membrane extracts (BMEs) that are most commonly acquired commercially. Each clinical site utilizes distinct BME lots and may be restricted due to the availability of commercial BME sources. However, the impact of different sources and lots of BMEs on organoid drug response is unknown. Here, we tested the impact of BME source and lot on proliferation, chemotherapy and targeted therapy drug response, and gene expression in mouse and human pancreatic ductal adenocarcinoma (PDA) organoids. Both human and mouse organoids displayed increased proliferation in Matrigel (Corning) compared to Cultrex (RnD) and UltiMatrix (RnD). However, we observed no substantial impact on drug response when oragnoids were cultured in Matrigel, Cultrex, or UltiMatrix. We also did not observe major shifts in gene expression across the different BME sources, and PDOs maintained their Classical or Basal-like designation. Overall, we find that BME source (Matrigel, Cultrex, UltiMatrix) does not shift PDO dose-response curves and drug testing results, indicating that PDO pharmacotyping is a robust approach for precision medicine.

5.
J Exp Med ; 219(6)2022 06 06.
Article in English | MEDLINE | ID: mdl-35522218

ABSTRACT

Pancreatic ductal adenocarcinoma (PDA) is one of the deadliest cancers and is projected to soon be the second leading cause of cancer death. Median survival of PDA patients is 6-10 mo, with the majority of diagnoses occurring at later, metastatic stages that are refractory to treatment and accompanied by worsening prognoses. Glycosylation is one of the most common types of post-translational modifications. The complex landscape of glycosylation produces an extensive repertoire of glycan moieties, glycoproteins, and glycolipids, thus adding a dynamic and tunable level of intra- and intercellular signaling regulation. Aberrant glycosylation is a feature of cancer progression and influences a broad range of signaling pathways to promote disease onset and progression. However, despite being so common, the functional consequences of altered glycosylation and their potential as therapeutic targets remain poorly understood and vastly understudied in the context of PDA. In this review, the functionality of glycans as they contribute to hallmarks of PDA are highlighted as active regulators of disease onset, tumor progression, metastatic capability, therapeutic resistance, and remodeling of the tumor immune microenvironment. A deeper understanding of the functional consequences of altered glycosylation will facilitate future hypothesis-driven studies and identify novel therapeutic strategies in PDA.


Subject(s)
Carcinoma, Pancreatic Ductal , Pancreatic Neoplasms , Carcinoma, Pancreatic Ductal/metabolism , Glycosylation , Humans , Pancreatic Neoplasms/pathology , Polysaccharides/metabolism , Tumor Microenvironment , Pancreatic Neoplasms
6.
J Neuroinflammation ; 17(1): 346, 2020 Nov 18.
Article in English | MEDLINE | ID: mdl-33208156

ABSTRACT

BACKGROUND: Glioblastoma is the most common and deadly form of primary brain cancer, accounting for more than 13,000 new diagnoses annually in the USA alone. Microglia are the innate immune cells within the central nervous system, acting as a front-line defense against injuries and inflammation via a process that involves transformation from a quiescent to an activated phenotype. Crosstalk between GBM cells and microglia represents an important axis to consider in the development of tissue engineering platforms to examine pathophysiological processes underlying GBM progression and therapy. METHODS: This work used a brain-mimetic hydrogel system to study patient-derived glioblastoma specimens and their interactions with microglia. Here, glioblastoma cells were either cultured alone in 3D hydrogels or in co-culture with microglia in a manner that allowed secretome-based signaling but prevented direct GBM-microglia contact. Patterns of GBM cell invasion were quantified using a three-dimensional spheroid assay. Secretome and transcriptome (via RNAseq) were used to profile the consequences of GBM-microglia interactions. RESULTS: Microglia displayed an activated phenotype as a result of GBM crosstalk. Three-dimensional migration patterns of patient-derived glioblastoma cells showed invasion was significantly decreased in response to microglia paracrine signaling. Potential molecular mechanisms underlying with this phenotype were identified from bioinformatic analysis of secretome and RNAseq data. CONCLUSION: The data demonstrate a tissue engineered hydrogel platform can be used to investigate crosstalk between immune cells of the tumor microenvironment related to GBM progression. Such multi-dimensional models may provide valuable insight to inform therapeutic innovations to improve GBM treatment.


Subject(s)
Brain Neoplasms/metabolism , Gelatin/administration & dosage , Glioblastoma/metabolism , Hydrogels/administration & dosage , Microglia/metabolism , Tumor Microenvironment/physiology , Animals , Brain Neoplasms/pathology , Cell Line , Coculture Techniques , Female , Glioblastoma/pathology , Humans , Male , Mice , Mice, Inbred C57BL , Mice, Nude , Microglia/drug effects , Neoplasm Invasiveness/pathology , Tissue Engineering/methods , Tumor Cells, Cultured , Tumor Microenvironment/drug effects , Xenograft Model Antitumor Assays/methods
7.
Curr Opin Behav Sci ; 28: 44-50, 2019 Aug.
Article in English | MEDLINE | ID: mdl-31049368

ABSTRACT

A malignant brain tumor diagnosis is often accompanied with intense feelings and can be associated with psychosocial conditions including depression, anxiety, and/or increased distress levels. Previous work has highlighted the impact of uncontrolled psychological distress among brain tumor patients. Given the negative impact of maladaptive psychosocial and biobehavioral factors on normal immune system functions, the question remains as to how psychological conditions potentially affect the brain tumor patient anti-tumor immune response. Since immunotherapy has yet to show efficacy at increasing malignant glioma patient survival in all randomized, phase III clinical trials to-date, this review provides new insights into the potential negative effects of chronic distress on brain tumor patient immune functions and outcomes.

8.
Biomater Sci ; 6(4): 854-862, 2018 Mar 26.
Article in English | MEDLINE | ID: mdl-29485655

ABSTRACT

Glioblastoma (GBM) is the most common, aggressive, and deadly form of adult brain cancer, and is associated with a short survival rate (median 12-15 months, 5+ year less than 5%). The complex tumor microenvironment includes matrix transitions at the tumor margin, such as gradations in hyaluronic acid (HA). In addition, metabolic stress induced by decreased oxygen content across the tumor may contribute to tumor progression. However, cross-talk between matrix composition and metabolic stress remains unclear. In this study, we fabricated an in vitro brain memetic HA-decorated gelatin hydrogel platform incorporating variable oxygen concentrations to mimic intra-tumoral hypoxia. We observed that EGFR status (wildtype vs. a constitutively active EGFRvIII mutant) of U87 GBM cells affected proliferation and metabolic activity in response to hypoxia and matrix-bound HA. The use of an invasion assay revealed that invasion was significantly enhanced in both cell types under hypoxia. Moreover, we observed compensatory secretion of soluble HA in cases of enhanced GBM cell invasion, consistent with our previous findings using other GBM cell lines. Interestingly, U87 GBM cells adapted to hypoxia by shifting toward a more anaerobic metabolic state, a mechanism that may contribute to GBM cell invasion. Collectively, these data demonstrate that the use of a three-dimensional hydrogel provides a robust method to study the impact of matrix composition and metabolic challenges on GBM cell invasion, a key factor contributing to the most common, aggressive, and deadly form of adult brain cancer.


Subject(s)
Biomimetic Materials/chemistry , Cell Proliferation , Glioblastoma/metabolism , Hyaluronic Acid/metabolism , Oxygen/metabolism , Cell Hypoxia , Cell Line, Tumor , ErbB Receptors/metabolism , Gelatin/chemistry , Humans , Hyaluronic Acid/chemistry , Hydrogels/chemistry , Oxygen/chemistry
9.
J Nutr ; 147(8): 1524-1530, 2017 08.
Article in English | MEDLINE | ID: mdl-28659405

ABSTRACT

Background: Epidemiologic, clinical, and experimental studies have suggested that fish oil (FO), a rich source of n-3 (ω-3) polyunsaturated fatty acids, protects against colon cancer. However, this message is confounded by the FDA's warning that the consumption of certain types of fish should be restricted because of contamination with persistent organic pollutants (POPs), such as polychlorinated biphenyls (PCBs) and organochlorine pesticides.Objective: We examined FO contaminated with POPs (PCBs, dichlorodiphenyltrichloroethane, and chlordane) compared with unmodified FO on the risk factors of colon cancer development.Methods: Male Sprague-Dawley rats aged 28 d (n = 30) were allocated into 3 groups and fed 15% corn oil (CO), FO, or POP-contaminated FO for 9 wk with a subcutaneous injection of colon carcinogen azoxymethane at weeks 3 and 4. Colonic aberrant crypt foci (ACF) and cell proliferation were enumerated, and the gene expression of inflammation, antioxidant enzymes, and repair enzymes were determined with the use of real-time quantitative polymerase chain reaction analysis.Results: FO-fed rats had a lower number of ACF (mean ± SE: 29 ± 4.0 for FO compared with 53 ± 8.4 for CO and 44 ± 4.6 for POP FO) and higher-multiplicity ACF than the CO and POP FO groups (4.7 ± 0.9 for FO compared with 11 ± 1.5 for CO and 9.6 ± 1.8 for POP FO) (P < 0.05). FO feeding lowered the proliferation index compared with the CO and POP FO feeding groups (18% ± 1.1% for FO compared with 25% ± 1.6% for CO and 23% ± 0.7% for POP FO) (P = 0.009). Superoxide dismutase [2.4 ± 0.6 relative quantification (RQ) for FO compared with 1.2 ± 0.2 RQ for CO and 1.3 ± 0.3 RQ for POP FO] and catalase gene expression (10 ± 2.0 RQ for FO compared with 5.4 ± 1.1 RQ for CO and 6.6 ± 1.5 RQ for POP FO) were higher in the FO group than in the CO and POP FO groups (P < 0.05). There were no differences between CO and POP FO on the variables.Conclusion: These results indicate that POPs in FO reduce the preventive effects of FO on colon carcinogenesis by increasing preneoplastic lesion formation through the downregulation of antioxidant enzyme expression and increasing cell proliferation in rats.


Subject(s)
Antioxidants/metabolism , Colon/drug effects , Colonic Neoplasms/prevention & control , Drug Contamination , Fish Oils , Intestinal Mucosa/drug effects , Water Pollutants, Chemical/adverse effects , Animals , Azoxymethane , Catalase/genetics , Catalase/metabolism , Cell Proliferation , Colon/pathology , Colonic Neoplasms/chemically induced , Colonic Neoplasms/pathology , Dietary Supplements , Down-Regulation , Fish Oils/chemistry , Fish Oils/therapeutic use , Fishes , Gene Expression , Intestinal Mucosa/pathology , Male , Pesticides/adverse effects , Polychlorinated Biphenyls/adverse effects , Rats, Sprague-Dawley , Superoxide Dismutase/genetics , Superoxide Dismutase/metabolism
10.
Article in English | MEDLINE | ID: mdl-30581989

ABSTRACT

Diet and nutrition are undeniably two factors that have a major impact on the prevention, progression, and treatment of various cancers. In this review, we will discuss how bioactives from diet and nutritional status affect each of the hallmarks of cancer. We will present recent research and discuss using diet and nutrition as a means to prevent and treat cancer.

11.
J Nutr ; 145(5): 939-44, 2015 May.
Article in English | MEDLINE | ID: mdl-25788582

ABSTRACT

BACKGROUND: Numerous studies have investigated the benefits of fish, fish oil, and ω-3 (n-3) polyunsaturated fatty acids against cardiovascular diseases. However, concern surrounding contamination with persistent organic pollutants (POPs) prompts caution in the recommendation to consume fish and fish oil. OBJECTIVE: The present study compared the effects of fish oil contaminated with polychlorinated biphenyls (PCBs) and organochlorine pesticides (OCs) on serum lipid profiles, inflammation, and oxidative stress. METHODS: Twenty eight-day-old male Sprague-Dawley rats (n = 30) consumed diets of unmodified fish oil (FO) consisting of 15% fat by weight, persistent organic pollutant-contaminated fish oil (POP FO) (PCBs at 2.40 µg/g; OCs at 3.80 µg/g FO), or corn oil (control; CO) for 9 wk. Lipid profiles and C-reactive protein concentrations were assessed. Hepatic gene expression related to lipid metabolism was determined by real time quantitative polymerase chain reaction analysis. RESULTS: After 9 wk of feeding, accumulation of PCBs and OCs in the fat tissue of the POP FO group compared with the other 2 groups was confirmed (P < 0.01). Both fish oil groups showed greater HDL cholesterol (FO 53 ± 5.3 and POP FO 55 ± 7.7 vs. CO 34 ± 2.3 mg/dL), but lower triglycerides (24 ± 2.8 and 22 ± 3.0 vs. 43 ± 5.6 mg/dL), LDL cholesterol (38 ± 14 and 34 ± 9.2 vs. 67 ± 4.4 mg/dL), and C-reactive protein (113 ± 20 and 120 ± 26 vs. 189 ± 22 µg/dL) compared with the CO group (P < 0.05). Gene expression of fatty acid synthase in both fish oil groups was also less than in the CO group (P < 0.05). However, the POP FO group showed greater lipid peroxidation (5.1 ± 0.7 vs. 2.9 ± 0.9 and 2.6 ± 0.6 µM) and less antioxidant capacity (0.08 ± 0.06 vs. 0.5 ± 0.1 and 0.4 ± 0.1 mM) than the CO and FO groups (P < 0.05). CONCLUSIONS: These findings indicate that, despite exhibiting benefits on serum lipid concentrations and inflammation, contamination with PCBs and OCs showed significant negative effects on oxidative stress and antioxidant capacity in rats. Future studies should investigate the effects of different contaminant doses and the possibility of a dose-dependent response, a lengthened feeding time, and interactions between contaminant mixtures and oils of varying composition to advise on dietary consumption of fish and fish oil.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Dietary Supplements , Environmental Pollutants/toxicity , Fish Oils/therapeutic use , Food Contamination , Hypolipidemic Agents/therapeutic use , Oxidative Stress , Adipose Tissue, White/chemistry , Adipose Tissue, White/drug effects , Adipose Tissue, White/immunology , Adipose Tissue, White/metabolism , Animals , Anti-Inflammatory Agents, Non-Steroidal/adverse effects , Anti-Inflammatory Agents, Non-Steroidal/chemistry , C-Reactive Protein/analysis , Dietary Supplements/adverse effects , Drug Residues/analysis , Drug Residues/toxicity , Environmental Pollutants/analysis , Environmental Pollutants/metabolism , Epididymis , Fatty Acid Synthases/genetics , Fatty Acid Synthases/metabolism , Fish Oils/adverse effects , Fish Oils/chemistry , Gene Expression Regulation, Enzymologic/drug effects , Hydrocarbons, Chlorinated/analysis , Hydrocarbons, Chlorinated/metabolism , Hydrocarbons, Chlorinated/toxicity , Hydroxymethylglutaryl CoA Reductases/genetics , Hydroxymethylglutaryl CoA Reductases/metabolism , Hyperlipidemias/blood , Hyperlipidemias/immunology , Hyperlipidemias/metabolism , Hyperlipidemias/prevention & control , Hypolipidemic Agents/adverse effects , Hypolipidemic Agents/chemistry , Lipid Peroxidation/drug effects , Liver/chemistry , Liver/drug effects , Liver/immunology , Liver/metabolism , Male , Oxidative Stress/drug effects , Polychlorinated Biphenyls/analysis , Polychlorinated Biphenyls/metabolism , Polychlorinated Biphenyls/toxicity , Rats, Sprague-Dawley
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