Michael D. Henry

University of Iowa

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Devon L. Moose

University of Iowa

Kevin P. Campbell

University of Iowa

Jones T. Nauseef

Cornell University

Marion Vanneste

University of Iowa

Patrick Breheny

University of Iowa

Toshinori Hoshi

California University of Pennsylvania

Wei Cao

The University of Texas Health Science Center at Houston

Courtney Yong

Indiana University – Purdue University Indianapolis

Thomas S. Griffith

University of Minnesota Medical Center

Qing Zhou

Guangdong Provincial People's Hospital

Cooperative Institutions

University of Iowa

University of Iowa Hospitals and Clinics

University of Iowa Holden Comprehensive Cancer Center

Iowa City Public Library

Howard Hughes Medical Institute

University of Minnesota

University of Iowa Health Care

University of Pennsylvania

Radiation Oncology Associates

Peking University

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Development and comparison of novel bioluminescent mouse models of pancreatic neuroendocrine neoplasm metastasis

Scientific Reports (2021)

Courtney A. Kaemmer Shaikamjad Umesalma Chandra K. Maharjan Devon L. Moose Goutham Narla

Abstract Pancreatic neuroendocrine neoplasms (pNENs) are slow growing cancers of increasing incidence that lack effective treatments once they become metastatic. Unfortunately, nearly half of pNEN patients present with metastatic liver tumors at diagnosis and current therapies fail to improve overall survival. Pre-clinical models of pNEN metastasis are needed to advance our understanding of the mechanisms driving the metastatic process and for the development of novel, targeted therapeutic interventions. To model metastatic dissemination of tumor cells, human pNEN cell lines (BON1 and Qgp1) stably expressing firefly luciferase (luc) were generated and introduced into NSG immunodeficient mice by intracardiac (IC) or intravenous (IV) injection. The efficiency, kinetics and distribution of tumor growth was evaluated weekly by non-invasive bioluminescent imaging (BLI). Tumors formed in all animals in both the IC and IV models. Bioluminescent Qgp1.luc cells preferentially metastasized to the liver regardless of delivery route, mimicking the predominant site of pNEN metastasis in patients. By comparison, BON1.luc cells most commonly formed lung tumors following either IV or IC administration and colonized a wider variety of tissues than Qgp1.luc cells. These models provide a unique platform for testing candidate metastasis genes and anti-metastatic therapies for pNENs.

Bioluminescence imaging

10.1038/s41598-021-89866-1

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Citations (5)

rMATS: Robust and flexible detection of differential alternative splicing from replicate RNA-Seq data

Proceedings of the National Academy of Sciences (2014)

Shihao Shen Juw Won Park Zhixiang Lu Lan Lin Michael D. Henry

Significance Alternative splicing (AS) is an important mechanism of eukaryotic gene regulation. Deep RNA sequencing (RNA-Seq) has become a powerful approach for quantitative profiling of AS. With the increasing capacity of high-throughput sequencers, it has become common for RNA-Seq studies of AS to examine multiple biological replicates. We developed rMATS, a new statistical method for robust and flexible detection of differential AS from replicate RNA-Seq data. Besides the analysis of unpaired replicates, rMATS includes a model specifically designed for paired replicates, such as case–control matched pairs in clinical RNA-Seq datasets. We expect rMATS will be useful for genome-wide studies of AS in diverse research projects. Our data also provide new insights about the experimental design for RNA-Seq studies of AS.

Replicate

RNA-Seq

10.1073/pnas.1419161111

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Citations (2,175)

Resistance to Fluid Shear Stress Is a Conserved Biophysical Property of Malignant Cells

PLoS ONE (2012)

J. Matthew Barnes Jones T. Nauseef Michael D. Henry

During metastasis, cancer cells enter the circulation in order to gain access to distant tissues, but how this fluid microenvironment influences cancer cell biology is poorly understood. A longstanding view is that circulating cancer cells derived from solid tissues may be susceptible to damage from hemodynamic shear forces, contributing to metastatic inefficiency. Here we report that compared to non-transformed epithelial cells, transformed cells are remarkably resistant to fluid shear stress (FSS) in a microfluidic protocol, exhibiting a biphasic decrease in viability when subjected to a series of millisecond pulses of high FSS. We show that magnitude of FSS resistance is influenced by several oncogenes, is an adaptive and transient response triggered by plasma membrane damage and requires extracellular calcium and actin cytoskeletal dynamics. This novel property of malignant cancer cells may facilitate hematogenous metastasis and indicates, contrary to expectations, that cancer cells are quite resistant to destruction by hemodynamic shear forces.

10.1371/journal.pone.0050973

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Citations (175)

High content screening identifies monensin as an EMT-selective cytotoxic compound

Scientific Reports (2019)

Marion Vanneste Qin Huang Mengshi Li Devon L. Moose Lei Zhao

Abstract Epithelial-to-mesenchymal transition (EMT) is implicated in cancer metastasis and drug resistance. Specifically targeting cancer cells in an EMT-like state may have therapeutic value. In this study, we developed a cell imaging-based high-content screening protocol to identify EMT-selective cytotoxic compounds. Among the 2,640 compounds tested, salinomycin and monensin, both monovalent cation ionophores, displayed a potent and selective cytotoxic effect against EMT-like cells. The mechanism of action of monensin was further evaluated. Monensin (10 nM) induced apoptosis, cell cycle arrest, and an increase in reactive oxygen species (ROS) production in TEM 4-18 cells. In addition, monensin rapidly induced swelling of Golgi apparatus and perturbed mitochondrial function. These are previously known effects of monensin, albeit occurring at much higher concentrations in the micromolar range. The cytotoxic effect of monensin was not blocked by inhibitors of ferroptosis. To explore the generality of our findings, we evaluated the toxicity of monensin in 24 human cancer cell lines and classified them as resistant or sensitive based on IC 50 cutoff of 100 nM. Gene Set Enrichment Analysis identified EMT as the top enriched gene set in the sensitive group. Importantly, increased monensin sensitivity in EMT-like cells is associated with elevated uptake of 3 H-monensin compared to resistant cells.

Monensin

Salinomycin

10.1038/s41598-018-38019-y

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Citations (31)

Eradication of Metastatic Renal Cell Carcinoma after Adenovirus-Encoded TNF-Related Apoptosis-Inducing Ligand (TRAIL)/CpG Immunotherapy

PLoS ONE (2012)

Lyse A. Norian Timothy P. Kresowik Henry Rosevear Britnie R. James Timothy R. Rosean

Despite evidence that antitumor immunity can be protective against renal cell carcinoma (RCC), few patients respond objectively to immunotherapy and the disease is fatal once metastases develop. We asked to what extent combinatorial immunotherapy with Adenovirus-encoded murine TNF-related apoptosis-inducing ligand (Ad5mTRAIL) plus CpG oligonucleotide, given at the primary tumor site, would prove efficacious against metastatic murine RCC. To quantitate primary renal and metastatic tumor growth in mice, we developed a luciferase-expressing Renca cell line, and monitored tumor burdens via bioluminescent imaging. Orthotopic tumor challenge gave rise to aggressive primary tumors and lung metastases that were detectable by day 7. Intra-renal administration of Ad5mTRAIL+CpG on day 7 led to an influx of effector phenotype CD4 and CD8 T cells into the kidney by day 12 and regression of established primary renal tumors. Intra-renal immunotherapy also led to systemic immune responses characterized by splenomegaly, elevated serum IgG levels, increased CD4 and CD8 T cell infiltration into the lungs, and elimination of metastatic lung tumors. Tumor regression was primarily dependent upon CD8 T cells and resulted in prolonged survival of treated mice. Thus, local administration of Ad5mTRAIL+CpG at the primary tumor site can initiate CD8-dependent systemic immunity that is sufficient to cause regression of metastatic lung tumors. A similar approach may prove beneficial for patients with metastatic RCC.

Primary tumor

10.1371/journal.pone.0031085

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Citations (49)

Prolyl-4-Hydroxylase 3 (PHD3) Expression Is Downregulated during Epithelial-to-Mesenchymal Transition

PLoS ONE (2013)

Trenton L. Place Jones T. Nauseef Peterson Kariuki Maina Michael D. Henry James J. Mezhir

Prolyl-4-hydroxylation by the intracellular prolyl-4-hydroxylase enzymes (PHD1-3) serves as a master regulator of environmental oxygen sensing. The activity of these enzymes is tightly tied to tumorigenesis, as they regulate cell metabolism and angiogenesis through their control of hypoxia-inducible factor (HIF) stability. PHD3 specifically, is gaining attention for its broad function and rapidly accumulating array of non-HIF target proteins. Data from several recent studies suggest a role for PHD3 in the regulation of cell morphology and cell migration. In this study, we aimed to investigate this role by closely examining the relationship between PHD3 expression and epithelial-to-mesenchymal transition (EMT); a transcriptional program that plays a major role in controlling cell morphology and migratory capacity. Using human pancreatic ductal adenocarcinoma (PDA) cell lines and Madin-Darby Canine Kidney (MDCK) cells, we examined the correlation between several markers of EMT and PHD3 expression. We demonstrated that loss of PHD3 expression in PDA cell lines is highly correlated with a mesenchymal-like morphology and an increase in cell migratory capacity. We also found that induction of EMT in MDCK cells resulted in the specific downregulation of PHD3, whereas the expression of the other HIF-PHD enzymes was not affected. The results of this study clearly support a model by which the basal expression and hypoxic induction of PHD3 is suppressed by the EMT transcriptional program. This may be a novel mechanism by which migratory or metastasizing cells alter signaling through specific pathways that are sensitive to regulation by O2. The identification of downstream pathways that are affected by the suppression of PHD3 expression during EMT may provide important insight into the crosstalk between O2 and the migratory and metastatic potential of tumor cells.

Hydroxylation

Cell fate determination

10.1371/journal.pone.0083021

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Citations (8)

Locally invasive, castrate-resistant prostate cancer in a Pten/Trp53 double knockout mouse model of prostate cancer monitored with non-invasive bioluminescent imaging

PLoS ONE (2020)

Courtney Yong Devon L. Moose Nadine Bannick Wade R. Gutierrez Marion Vanneste

Here we have improved an existing mouse model of prostate cancer based on prostate-specific deletion of Pten and Trp53 by incorporating a Cre-activatable luciferase reporter. By coupling the deletion of those genes to the activation of a luciferase reporter, we were able to monitor tumor burden non-invasively over time. We show that, consistent with previous reports, deletion of both Pten and Trp53 on a C57BL/6 background accelerates tumor growth and results in both the loss of androgen receptor expression and castrate resistant tumors as compared with loss of Pten alone. Loss of Trp53 results in the development of sarcomatoid histology and the expression of markers of epithelial-to-mesenchymal transition Zeb1 and vimentin, with kinetics and penetrance dependent on whether one or both alleles of Trp53 were deleted. Homozygous deletion of Trp53 and Pten resulted in uniformly lethal disease by 25 weeks. While we were able to detect locally invasive disease in the peritoneal cavity in aggressive tumors from the double knockout mice, we were unable to detect lymphatic or hematogenous metastatic disease in lymph nodes or at distant sites.

Knockout mouse

10.1371/journal.pone.0232807

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Citations (7)

Identification of blood lipid markers of docetaxel treatment in prostate cancer patients

Scientific Reports (2024)

Morgan C. Finnerty Franklin E. Leach Yousef Zakharia Kenneth G. Nepple Michael G. Bartlett

Identification

10.1038/s41598-024-73074-8

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Citations (0)

Deletion of brain dystroglycan recapitulates aspects of congenital muscular dystrophy

Nature (2002)

Steven A. Moore Fumiaki Saito Jianguo Chen Daniel E. Michele Michael D. Henry

Dystroglycan

Congenital muscular dystrophy

10.1038/nature00838

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Citations (562)

Pharmacological ascorbate inhibits pancreatic cancer metastases via a peroxide-mediated mechanism

Scientific Reports (2020)

Brianne R. O’Leary Matthew S. Alexander Juan Du Devon L. Moose Michael D. Henry

Pharmacological ascorbate (P-AscH-, high-dose, intravenous vitamin C) is cytotoxic to tumor cells in doses achievable in humans. Phase I studies in pancreatic cancer (PDAC) utilizing P-AscH- have demonstrated increases in progression free survival, suggesting a reduction in metastatic disease burden. The purpose of this study was to determine the effects of P-AscH- on metastatic PDAC. Several in vitro and in vivo mechanisms involved in PDAC metastases were investigated following treatment with P-AscH-. Serum from PDAC patients in clinical trials with P-AscH- were tested for the presence and quantity of circulating tumor cell-derived nucleases. P-AscH- inhibited invasion, basement membrane degradation, decreased matrix metalloproteinase expression, as well as clonogenic survival and viability during exposure to fluid shear stress. In vivo, P-AscH- significantly decreased formation of ascites, tumor burden over time, circulating tumor cells, and hepatic metastases. Both in vitro and in vivo findings were reversed with the addition of catalase suggesting that the effect of P-AscH- on metastatic disease is mediated by hydrogen peroxide. Finally, P-AscH- decreased CTC-derived nucleases in subjects with stage IV PDAC in a phase I clinical trial. We conclude that P-AscH- attenuates the metastatic potential of PDAC and may prove to be effective for treating advanced disease.

Peroxide

10.1038/s41598-020-74806-2

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Citations (21)