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Item A multidimensional platform of patient-derived tumors identifies drug susceptibilities for clinical lenvatinib resistance(Elsevier, 2024) Sun, Lei; Wan, Arabella H.; Yan, Shijia; Liu, Ruonian; Li, Jiarui; Zhou, Zhuolong; Wu, Ruirui; Chen, Dongshi; Bu, Xianzhang; Ou, Jingxing; Li, Kai; Lu, Xiongbin; Wan, Guohui; Ke, Zunfu; Medical and Molecular Genetics, School of MedicineLenvatinib, a second-generation multi-receptor tyrosine kinase inhibitor approved by the FDA for first-line treatment of advanced liver cancer, facing limitations due to drug resistance. Here, we applied a multidimensional, high-throughput screening platform comprising patient-derived resistant liver tumor cells (PDCs), organoids (PDOs), and xenografts (PDXs) to identify drug susceptibilities for conquering lenvatinib resistance in clinically relevant settings. Expansion and passaging of PDCs and PDOs from resistant patient liver tumors retained functional fidelity to lenvatinib treatment, expediting drug repurposing screens. Pharmacological screening identified romidepsin, YM155, apitolisib, NVP-TAE684 and dasatinib as potential antitumor agents in lenvatinib-resistant PDC and PDO models. Notably, romidepsin treatment enhanced antitumor response in syngeneic mouse models by triggering immunogenic tumor cell death and blocking the EGFR signaling pathway. A combination of romidepsin and immunotherapy achieved robust and synergistic antitumor effects against lenvatinib resistance in humanized immunocompetent PDX models. Collectively, our findings suggest that patient-derived liver cancer models effectively recapitulate lenvatinib resistance observed in clinical settings and expedite drug discovery for advanced liver cancer, providing a feasible multidimensional platform for personalized medicine.Item Body Mass Index Trajectories, Weight Gain, and Risks of Liver and Biliary Tract Cancers(Oxford University Press, 2022-08-12) Yang, Wanshui; Zeng, Xufen; Petrick, Jessica L.; Danford, Christopher J.; Florio, Andrea A.; Lu, Bing; Nan, Hongmei; Ma, Jiantao; Wang, Liang; Zeng, Hongmei; Sudenga, Staci L.; Campbell, Peter T.; Giovannucci, Edward; McGlynn, Katherine A.; Zhang, Xuehong; Epidemiology, School of Public HealthBackground: Little is known about the role of early obesity or weight change during adulthood in the development of liver cancer and biliary tract cancer (BTC). Methods: We investigated the associations of body mass index (BMI) and weight trajectories with the risk of liver cancer and BTC in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO). BMI was self-reported at ages 20, 50, and at enrollment. BMI trajectories were determined using latent class growth models. Cox regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Results: During a median follow-up of 15.9 years among 138,922 participants, 170 liver cancer and 143 BTC cases were identified. Compared with those whose BMI does not exceed 25 kg/m2, participants with BMI exceeding 25 kg/m2 at age 20 had increased risks of liver cancer (HR = 2.03, 95% CI: 1.26-3.28) and BTC (HR = 1.99, 95% CI: 1.16-3.39). Compared to participants maintaining normal BMI until enrollment, trajectory of normal weight at age 20 to obesity at enrollment was associated with increased risk for liver cancer (HR = 2.50, 95% CI: 1.55-4.04) and BTC (HR = 1.83, 95% CI: 1.03-3.22). Compared to adults with stable weight (+/-5kg) between age 20 to 50 years, weight gain ≥20 kg between ages 20 to 50 years had higher HRs of 2.24 (95%CI: 1.40-3.58) for liver cancer and 1.86 (95% CI: 1.12-3.09) for BTC. Conclusions: Being overweight/obese at age 20, and BMI trajectories that result in being overweight and/or obese, may increase risk for both liver cancer and BTC.Item Epigenetic aberrations of gene expression in a rat model of hepatocellular carcinoma(Taylor & Francis, 2022) Boycott, Cayla; Beetch, Megan; Yang, Tony; Lubecka, Katarzyna; Ma, Yuexi; Zhang, Jiaxi; Kurzava Kendall, Lucinda; Ullmer, Melissa; Ramsey, Benjamin S.; Torregrosa-Allen, Sandra; Elzey, Bennett D.; Cox, Abigail; Lanman, Nadia Atallah; Hui, Alisa; Villanueva, Nathaniel; de Conti, Aline; Huan, Tao; Pogribny, Igor; Stefanska, Barbara; Anatomy, Cell Biology and Physiology, School of MedicineHepatocellular carcinoma (HCC) is mostly triggered by environmental and life-style factors and may involve epigenetic aberrations. However, a comprehensive documentation of the link between the dysregulated epigenome, transcriptome, and liver carcinogenesis is lacking. In the present study, Fischer-344 rats were fed a choline-deficient (CDAA, cancer group) or choline-sufficient (CSAA, healthy group) L-amino acid-defined diet. At the end of 52 weeks, transcriptomic alterations in livers of rats with HCC tumours and healthy livers were investigated by RNA sequencing. DNA methylation and gene expression were assessed by pyrosequencing and quantitative reverse-transcription PCR (qRT-PCR), respectively. We discovered 1,848 genes that were significantly differentially expressed in livers of rats with HCC tumours (CDAA) as compared with healthy livers (CSAA). Upregulated genes in the CDAA group were associated with cancer-related functions, whereas macronutrient metabolic processes were enriched by downregulated genes. Changes of highest magnitude were detected in numerous upregulated genes that govern key oncogenic signalling pathways, including Notch, Wnt, Hedgehog, and extracellular matrix degradation. We further detected perturbations in DNA methylating and demethylating enzymes, which was reflected in decreased global DNA methylation and increased global DNA hydroxymethylation. Four selected upregulated candidates, Mmp12, Jag1, Wnt4, and Smo, demonstrated promoter hypomethylation with the most profound decrease in Mmp12. MMP12 was also strongly overexpressed and hypomethylated in human HCC HepG2 cells as compared with primary hepatocytes, which coincided with binding of Ten-eleven translocation 1 (TET1). Our findings provide comprehensive evidence for gene expression changes and dysregulated epigenome in HCC pathogenesis, potentially revealing novel targets for HCC prevention/treatment.Item Hepatocellular Carcinoma : A Decade of Hospitalizations and Financial Burden in the United States(Elsevier, 2017-10) Jinjuvadia, Raxitkumar; Salami, Augustine; Lenhart, Adrienne; Jinjuvadia, Kartikkumar; Liangpunsakul, Suthat; Biochemistry and Molecular Biology, School of MedicineBACKGROUND: Despite a rise in the prevalence of hepatocellular carcinoma (HCC), data on HCC-related hospitalizations and financial burden are limited. The aim of this study was to evaluate temporal trends of HCC-related hospitalizations and evaluate its financial influence. MATERIALS AND METHODS: Patients with the diagnosis of HCC, as reported by International Classification of Diseases-Ninth Revision code, were identified from the National Inpatient Sample databases from 2002-2011. The national estimates of hospitalizations were derived using appropriate sample weights. The change in total average charges per each hospitalization over the study period was calculated after adjusting for inflation. RESULTS: Hospitalizations related to HCC have increased from 24,024 in 2002 to 50,609 in 2011. Of these admissions, HCC was the principal diagnosis in 10,762 and 16,350 subjects in 2002 and 2011, respectively. Most were white males (male: 70%; white: 55%). The overall inpatient mortality was significantly decreased from 13.5% in 2002 to 9.9% in 2011 (P < 0.01). The same trend was also observed for the length of hospital stay (6.5 versus 5.6 days in 2002 and 2011, respectively). The inflation-adjusted cost per hospitalization increased by approximately 47% during the study period. CONCLUSIONS: Despite the decrease in mortality rate and length-of-stay, hospitalizations and financial burden associated with HCC continued to increase between 2002 and 2011 in the United States.Item Older Age and Disease Duration Are Highly Associated with Hepatocellular Carcinoma in Patients with Autoimmune Hepatitis(Springer, 2019-01-07) Dakhoul, Lara; Jones, Keaton R.; Gawrieh, Samer; Ghabril, Marwan; McShane, Chelsey; Vuppalanchi, Raj; Vilar-Gomez, Eduardo; Nephew, Lauren; Chalasani, Naga; Lammert, Craig; Medicine, School of MedicineBackground: Hepatocellular carcinoma (HCC) is rare in patients with autoimmune hepatitis (AIH). However, the overall burden of AIH cirrhosis in causing HCC and patients' risk factors are not well understood. Aims: To characterize the proportion of HCC linked to AIH at a large academic health center, and to identify variables associated with HCC in patients with AIH in a case-control study design. Methods: Over a 14.5-year period, medical records of all patients with HCC were reviewed. Cases are AIH patients identified from the cohort, and controls are patients with AIH without HCC. Three controls were randomly chosen from the Genetic Repository of Autoimmune Liver Disease and Coexisting Exposures database for each eligible case. Results: Out of 1250 eligible patients, 20 were linked to AIH (1.6%). Their median age was 64 years, 40% men and 100% Caucasian. Ten percent of AIH patients did not have evidence of cirrhosis at HCC diagnosis. The proportion of HCCs due to AIH decreased during the time intervals of the study. Compared to controls, cases were more likely men (40.0% vs. 18%, p = 0.049), with longer AIH duration (median 16 years vs. 5 years, p = 0.004). Prolonged AIH duration (OR 1.68, p = 0.006) and older age (OR 1.15, p = 0.049) were risk factors for HCC. Conclusions: AIH is a rare cause (1.6%) for HCC in Midwestern USA with a decreasing trend over 14.5 years. Ten percent of AIH-HCC patients did not have cirrhosis at time of HCC diagnosis. Patients with prolonged duration of the disease and older age are at high risk to develop HCC.Item Role of Non-Coding RNAs in the Progression of Liver Cancer: Evidence from Experimental Models(MDPI, 2019-10-25) O’Brien, April; Zhou, Tianhao; Tan, Christopher; Alpini, Gianfranco; Glaser, Shannon; Medicine, School of MedicineLiver cancer is a devastating cancer that ranges from relatively rare (around 2% of all cancers in the United States) to commonplace (up to 50% of cancers in underdeveloped countries). Depending upon the stage of pathogenesis, prognosis, or functional liver tissue present, transplantation or partial hepatectomy may be the only available treatment option. However, due to the rise in metabolic syndrome and the increasing demand for livers, patients often wait months or years for available organs. Due to this shortage, doctors must have other treatment options available. One promising area of cancer research lies in understanding the role of regulatory non-coding RNAs (ncRNAs) as oncogenic drivers and potential targets for prospective therapies. While the role of these ncRNAs was not initially clear, many of them have since been recognized to function as important players in the regulation of gene expression, epigenetic modification, and signal transduction in both normal and cancer cell cycles. Dysregulation of these different ncRNA subtypes has been implicated in the pathogenesis and progression of many major cancers including hepatocellular carcinoma. This review summarizes current findings on the roles noncoding RNAs play in the progression of liver cancer and the various animal models used in current research to elucidate those data.Item Systematic Survey of the Role of IGF in the Link Between Diabetes and Cancer(Indiana University, 2018) Devanathan, Nirupama; Kimble-Hill, Ann C.; Department of Medicine, Indiana University School of MedicineEpidemiological studies have proposed a link between type II diabetes and cancer via the IGF/insulin signaling pathway, which includes insulin-like peptides (IGF1, IGF2, and insulin), insulin receptors (IR-A, IR-B, IGF1R, and hybrids), and insulin substrate proteins (IRS1-6). In this study, up- and down-regulation of various components in the IGF/insulin signaling pathway are compared to clinical outcomes for cancer patients; the components include diagnosis age, overall survival, tumor invasion and vascularization, and body mass index. It was found that the up-regulation of insulin growth Factor (IGF)/insulin components was associated with overall survival and tumor invasion and vascularization, while the down-regulation of equivalent components was not associated with clinical outcomes assessed in this study. Particularly, the up-regulation of DOK5, IGF2, and IRS2 in colorectal cancer and IGF1R in liver cancer is associated with significantly decreased overall survival. Functional aberrations in either of the two proteins in co-expression pairs were identified for each cancer and correlated with overall survival and diagnosis age. Specific biomarkers proposed in this study will be further analyzed to fine-tune consistent associations that can be translated to reliable prognostic standards for the roles of IGF/insulin signaling pathway modulations that promote cancer.Item The Emerging Role of Ferroptosis in Liver Cancers(MDPI, 2022-12-16) Casini, Arianna; Leone, Stefano; Vaccaro, Rosa; Vivacqua, Giorgio; Ceci, Ludovica; Pannarale, Luigi; Franchitto, Antonio; Onori, Paolo; Gaudio, Eugenio; Mancinelli, Romina; Medicine, School of MedicineLiver cancer represents a global health challenge with worldwide growth. Hepatocellular carcinoma (HCC) is the most common type of liver cancer. Indeed, approximately 90% of HCC cases have a low survival rate. Moreover, cholangiocarcinoma (CC) is another malignant solid tumor originating from cholangiocytes, the epithelial cells of the biliary system. It is the second-most common primary liver tumor, with an increasing course in morbidity and mortality. Tumor cells always show high metabolic levels, antioxidant modifications, and an increased iron uptake to maintain unlimited growth. In recent years, alterations in iron metabolism have been shown to play an important role in the pathogenesis of HCC. Several findings show that a diet rich in iron can enhance HCC risk. Hence, elevated iron concentration inside the cell may promote the development of HCC. Growing evidence sustains that activating ferroptosis may potentially block the proliferation of HCC cells. Even in CC, it has been shown that ferroptosis plays a crucial role in the treatment of tumors. Several data confirmed the inhibitory effect in cell growth of photodynamic therapy (PDT) that can induce reactive oxygen species (ROS) in CC, leading to an increase in malondialdehyde (MDA) and a decrease in intracellular glutathione (GSH). MDA and GSH depletion/modulation are crucial in inducing ferroptosis, suggesting that PDT may have the potential to induce this kind of cell death through these ways. A selective induction of programmed cell death in cancer cells is one of the main treatments for malignant tumors; thus, ferroptosis may represent a novel therapeutic strategy against HCC and CC.Item Tumor Lymphatic Interactions Induce CXCR2-CXCL5 Axis and Alter Cellular Metabolism and Lymphangiogenic Pathways to Promote Cholangiocarcinoma(MDPI, 2021-11-09) Roy, Sukanya; Kumaravel, Subhashree; Banerjee, Priyanka; White, Tori K.; O’Brien, April; Seelig, Catherine; Chauhan, Rahul; Ekser, Burcin; Bayless, Kayla J.; Alpini, Gianfranco; Glaser, Shannon S.; Chakraborty, Sanjukta; Surgery, School of MedicineCholangiocarcinoma (CCA), or cancer of bile duct epithelial cells, is a very aggressive malignancy characterized by early lymphangiogenesis in the tumor microenvironment (TME) and lymph node (LN) metastasis which correlate with adverse patient outcome. However, the specific roles of lymphatic endothelial cells (LECs) that promote LN metastasis remains unexplored. Here we aimed to identify the dynamic molecular crosstalk between LECs and CCA cells that activate tumor-promoting pathways and enhances lymphangiogenic mechanisms. Our studies show that inflamed LECs produced high levels of chemokine CXCL5 that signals through its receptor CXCR2 on CCA cells. The CXCR2-CXCL5 signaling axis in turn activates EMT (epithelial-mesenchymal transition) inducing MMP (matrix metalloproteinase) genes such as GLI, PTCHD, and MMP2 in CCA cells that promote CCA migration and invasion. Further, rate of mitochondrial respiration and glycolysis of CCA cells was significantly upregulated by inflamed LECs and CXCL5 activation, indicating metabolic reprogramming. CXCL5 also induced lactate production, glucose uptake, and mitoROS. CXCL5 also induced LEC tube formation and increased metabolic gene expression in LECs. In vivo studies using CCA orthotopic models confirmed several of these mechanisms. Our data points to a key finding that LECs upregulate critical tumor-promoting pathways in CCA via CXCR2-CXCL5 axis, which further augments CCA metastasis.