Melissa Fishel

Melissa Fishel
Indiana University School of Medicine | IUSOM · Department of Pediatrics

About

132
Publications
14,113
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3,636
Citations
Citations since 2016
83 Research Items
2383 Citations
20162017201820192020202120220100200300400500
20162017201820192020202120220100200300400500
20162017201820192020202120220100200300400500
20162017201820192020202120220100200300400500

Publications

Publications (132)
Article
Full-text available
Purpose/Objective(s) In pancreatic ductal adenocarcinoma (PDAC), hypoxia is key mediator of resistance to chemo-radiotherapy and a prominent feature of PDAC tumor microenvironment (TME). Heme oxygenase-1 (HMOX-1) is an Nrf2-regulated gene that plays a critical role in modulation of oxidative stress and ROS production. Previous research suggested th...
Article
Full-text available
Following publication of the original article [1], the authors noticed an error in Additional file 1. The incorrect Figure S5 was published. The corrected Additional file 1 is published in the correction and the original article [1] has been updated.
Article
Ref-1/APE1 (Redox factor-1, Ref-1; Apurinic/apyrimidinic endonuclease 1, APE1) is a redox signaling enzyme that biochemically converts several transcription factors (TFs), such as NF-kB, STAT3, HIF-1α from an oxidized to a reduced state, allowing TFs to bind DNA and activate various biological responses such as cell growth and inflammation. Ref-1 a...
Article
Malignant Peripheral Nerve Sheath Tumor (MPNST) is a rare soft tissue sarcoma common in patients with NF1 (neurofibromatosis type 1). MPNSTs respond poorly to most chemotherapeutics due to molecular heterogeneity and altered signal transduction pathways. Ref-1 and STAT3 are highly expressed in MPNST patient samples offering druggable pathways. Inhi...
Article
Pancreatic ductal adenocarcinoma (PDAC) exhibits one of the poorest prognoses of all solid cancers and is associated with very low overall and progression-free survival rate. Clinically, PDAC patient tumors show high expression levels of multiple components of the coagulation system (e.g., tissue factor, etc.) and fibrinolytic system, including uro...
Article
Full-text available
Background Colorectal cancer (CRC) consensus molecular subtypes (CMS) have different immunological, stromal cell, and clinicopathological characteristics. Single-cell characterization of CMS subtype tumor microenvironments is required to elucidate mechanisms of tumor and stroma cell contributions to pathogenesis which may advance subtype-specific t...
Article
Market drugs, such as Food and Drug Administration (FDA) or European Medicines Agency (EMA)-approved drugs for specific indications provide opportunities for repurposing for newer therapeutics. This potentially saves resources invested in clinical trials that verify drug safety and tolerance in humans prior to alternative indication approval. Prote...
Article
Full-text available
Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers with a poor response to current treatment regimens. The multifunctional DNA repair-redox signaling protein Ref-1 has a redox signaling function that activates several transcriptional factors (TFs) including NF-kB (RelA), STAT3, AP-1. These have been implicated in signaling in P...
Article
Full-text available
Background Pancreatic cancer is a complex disease with a desmoplastic stroma, extreme hypoxia, and inherent resistance to therapy. Understanding the signaling and adaptive response of such an aggressive cancer is key to making advances in therapeutic efficacy. Redox factor-1 (Ref-1), a redox signaling protein, regulates the conversion of several tr...
Article
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Acute myeloid leukaemia (AML) is an aggressive form of blood cancer that carries a dismal prognosis. Several studies suggest that the poor outcome is due to a small fraction of leukaemic cells that elude treatment and survive in specialised, oxygen (O2)-deprived niches of the bone marrow. Although several AML drug targets such as FLT3, IDH1/2 and C...
Article
Hypoxia is arguably the first recognized cancer microenvironment hallmark and affects virtually all cellular populations present in tumors. During the past decades the complex adaptive cellular responses to oxygen deprivation have been largely elucidated, raising hope for new anti cancer agents. Despite undeniable preclinical progress, therapeutic...
Article
Full-text available
In the era of precision medicine, radiation medicine is currently focused on the precise delivery of highly conformal radiation treatments. However, the tremendous developments in targeted therapy are yet to fulfill their full promise and arguably have the potential to dramatically enhance the radiation therapeutic ratio. The increased ability to m...
Article
Full-text available
The metabolic heterogeneity, and metabolic interplay between cells have been known as significant contributors to disease treatment resistance. However, with the lack of a mature high-throughput single-cell metabolomics technology, we have yet to establish systematic understanding of the intra-tissue metabolic heterogeneity and cooperative mechanis...
Conference Paper
Targeted therapy for cancer using small molecules has progressed exponentially, but agents that can affect cancer cells rather than non-tumorigenic cells are crucial to avoid pernicious side effects. AP endonuclease-1/Redox factor-1 (APE1/Ref-1 or Ref-1) is a multifunctional protein with DNA repair activity and redox signaling activity as major fun...
Conference Paper
Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers, with a five-year survival rate of less than ten percent. Kras is a common driver mutation of PDAC, contributing to progression and chemotherapy resistance. Additionally, inflammation is implicated in the development of PDAC and NFκB is recognized as a key mediator of inflammat...
Article
Full-text available
Hydrogels with dynamically tunable crosslinking are invaluable for directing stem cell fate and mimicking a stiffening matrix during fibrosis or tumor development. The increases in matrix stiffness during tissue development are often accompanied by the accumulation of extracellular matrices (e.g., collagen, hyaluronic acid (HA)), a phenomenon that...
Article
Full-text available
Background MPNST is a rare soft-tissue sarcoma that can arise from patients with NF1. Existing chemotherapeutic and targeted agents have been unsuccessful in MPNST treatment, and recent findings implicate STAT3 and HIF1-α in driving MPNST. The DNA-binding and transcriptional activity of both STAT3 and HIF1-α is regulated by Redox factor-1 (Ref-1) r...
Article
Pancreatic cancer can survive under the harshest of conditions including nutrient deprivation and extreme hypoxia. Its complex microenvironment contributes to PDAC’s (pancreatic ductal adenocarcinoma) therapeutic resistance and aggressive metastasis. Previous research shows that PDAC cells highly rely on increased glycolysis for ATP thereby limitin...
Article
Full-text available
In the realm of DNA repair, base excision repair (BER) protein, APE1/Ref-1 (Apurinic/Apyrimidinic Endonuclease 1/Redox Effector - 1, also called APE1) has been studied for decades. However, over the past decade, APE1 has been established as a key player in reduction-oxidation (redox) signaling. In the review by Caston et al. (The multifunctional AP...
Preprint
Full-text available
Background: Pancreatic cancer is a complex disease with a desmoplastic stroma, extreme hypoxia, and inherent resistance to therapy. Understanding the signaling and adaptive response of such an aggressive cancer is key to making advances in therapeutic efficacy. Redox factor-1 (Ref-1), a redox signaling protein, regulates the DNA binding activity of...
Article
Full-text available
With a plethora of molecularly targeted agents under investigation in cancer, a clear need exists to understand which pathways can be targeted simultaneously with multiple agents to elicit a maximal killing effect on the tumour. Combination therapy provides the most promise in difficult to treat cancers such as pancreatic. Ref‐1 is a multifunctiona...
Chapter
This chapter focuses on APE1 (AP endonuclease or redox factor 1; APE1/Ref-1, Ref-1 or APE1), which has multiple functions in DNA repair, transcriptional regulation, and RNA processing. APE1 is the endonuclease in base excision repair and also a major redox signaling factor for several important transcription factors that have been implicated in man...
Article
Full-text available
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Article
Full-text available
Apurinic/apyrimidinic (AP) endonuclease–reduction/oxidation factor 1 (APE1/Ref-1, also called APE1) is a multifunctional enzyme with crucial roles in DNA repair and reduction/oxidation (redox) signaling. APE1 was originally described as an endonuclease in the Base Excision Repair (BER) pathway. Further study revealed it to be a redox signaling hub...
Preprint
Full-text available
The metabolic heterogeneity, and metabolic interplay between cells and their microenvironment have been known as significant contributors to disease treatment resistance. Our understanding of the intra-tissue metabolic heterogeneity and cooperation phenomena among cell populations is unfortunately quite limited, without a mature single cell metabol...
Article
Full-text available
We hereby provide the initial portrait of lincNORS, a spliced lincRNA generated by the MIR193BHG locus, entirely distinct from the previously described miR-193b-365a tandem. While inducible by low O2 in a variety of cells and associated with hypoxia in vivo, our studies show that lincNORS is subject to multiple regulatory inputs, including estrogen...
Conference Paper
p>The Pancreatic Ductal Adenocarcinoma (PDAC) tumor microenvironment (TME) is comprised of numerous cell types. Among those, cancer associated fibroblasts (CAFs) play roles in tumor development, drug resistance, fibrosis and inflammation. GP130 cytokines, including Interleukin-6 (IL-6) and Leukemia Inhibitory Factor in the TME are implicated in pan...
Conference Paper
Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related death with a median survival time of 6-12 months. As most patients present with disseminated disease, the majority are offered palliative chemotherapy. With no approved treatment modalities for patients who progress on chemotherapy, we explored the effects of long-term Gem...
Article
Full-text available
Glioblastoma multiforme (GBM) is an incurable disease. Like most solid tumors, GBM harbors multiple overexpressed and mutated genes. Small molecules that selectively modulate these targets and their signaling pathways are expected to inhibit GBM phenotypes without affecting normal non-transformed cells. Phenotypic screening can be an effective stra...
Article
Full-text available
Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related death with a median survival time of 6–12 months. Most patients present with disseminated disease and the majority are offered palliative chemotherapy. With no approved treatment modalities for patients who progress on chemotherapy, we explored the effects of long-term gem...
Conference Paper
Full-text available
Malignant Peripheral Nerve Sheath Tumor (MPNST) is a rare soft tissue sarcoma that can arise from patients with NF1 (neurofibromatosis type 1). These patients are at a much greater risk of developing MPNST than the general population (10% vs. 0.01%, respectively). Existing chemotherapeutic and targeted agents have thus far not been successful in MP...
Article
Bladder cancer is the ninth most common cause of cancer-related deaths worldwide. Although cisplatin is used routinely in treating bladder cancer, refractory disease remains lethal for many patients. The recent addition of immunotherapy has improved patient outcomes; however, a large cohort of patients does not respond to these treatments. Therefor...
Article
Full-text available
A key challenge in modeling single-cell RNA-seq data is to capture the diversity of gene expression states regulated by different transcriptional regulatory inputs across individual cells, which is further complicated by largely observed zero and low expressions. We developed a left truncated mixture Gaussian (LTMG) model, from the kinetic relation...
Article
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive, incurable cancer with a 20% one-year survival rate. While standard-of-care therapy can prolong life in a small fraction of cases, PDAC is inherently resistant to current treatments and novel therapies are urgently required. Histone deacetylase (HDAC) inhibitors are effective in killing pancr...
Preprint
A key challenge in statistical modeling of single cell RNA-seq (scRNA-seq) data is to assess the multimodality of single gene expression with a simultaneous handling of the largely observed zero and low expressions. In this study, started from a mathematical derivation of the relationship between the mRNA abundance, transcriptional regulatory signa...
Article
Full-text available
Pancreatic ductal adenocarcinoma (PDAC) has reactive stroma that promotes tumor signaling, fibrosis, inflammation, and hypoxia, which activates HIF-1α to increase tumor cell metastasis and therapeutic resistance. Carbonic anhydrase IX (CA9) stabilizes intracellular pH following induction by HIF-1α. Redox effector factor-1 (APE1/Ref-1) is a multifun...
Article
Full-text available
While much progress has been made in the war on cancer, highly invasive cancers such as pancreatic cancer remain difficult to treat and anti-cancer clinical trial success rates remain low. One shortcoming of the drug development process that underlies these problems is the lack of predictive, pathophysiologically relevant preclinical models of inva...
Article
Full-text available
Ocular neovascular diseases like wet age-related macular degeneration are a major cause of blindness. Novel therapies are greatly needed for these diseases. One appealing antiangiogenic target is reduction-oxidation factor 1-apurinic/apyrimidinic endonuclease 1 (Ref-1/APE1). This protein can act as a redox-sensitive transcriptional activator for NF...
Article
Pancreatic ductal adenocarcinoma (PDAC) is the 4th leading cause of cancer-related mortality in the US. Most patients present with advanced disease and ~93% die within five years, with most surviving less than six months. Combination therapies including Gemcitabine (GemzarTM) and sustained release, nab-paclitaxel (AbraxaneTM) and FOLFIRINOX (5-FU/l...
Article
Full-text available
Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease characterized by aggressive metastasis and therapeutic resistance. Reactive stroma in PDAC tumors leads to fibrosis, inflammation, and hypoxia. Hypoxia signaling creates a more aggressive phenotype with increased potential for metastasis and decreased therapeutic efficacy. Carbonic anhydra...
Preprint
Full-text available
Ocular neovascular diseases like wet age-related macular degeneration are a major cause of blindness. Novel therapies are greatly needed for these diseases. One appealing antiangiogenic target is reduction-oxidation factor 1-apurinic/apyrimidinic endonuclease 1 (Ref-1/APE1). This protein can act as a redox-sensitive transcriptional activator for NF...
Article
Full-text available
Despite the increasingly recognized importance of the tumor microenvironment (TME) as a regulator of tumor progression, only few in vitro models have been developed to systematically study the effects of TME on tumor behavior in a controlled manner. Here we developed a three-dimensional (3D) in vitro model that recapitulates the physical and compos...
Data
Astrocytes and astrocyte conditioned media (ACM) increase the migration of GBM10 in a 3D brain-like matrix while only astrocytes increase 3D GBM43 migration. Presence of living astrocytes has a greater effect than ACM on 3D GBM migration. (A). Accumulated distance of migration during 15 h. (B). Net migration distance between initial (0 h) and final...
Data
Effect of STAT3 inhibitor SH-4-54 on STAT3 Tyr-705 phosphorylation in GBM43 and GBM10. SH-4-54 effectively decreases phosphorylation of STAT3 in the GBM43 cell line but has no effect on STAT3 activity in GBM10. Total protein loaded per lane 7 μg GBM10, 14 μg GBM43. (TIF)
Data
Comparison of GBM cell migration in 2D liquid culture vs 3D Col-HA matrix. (A). Accumulated distance of individual cell migration during 15 h. (B). Net migration distance between initial (0 h) and final migration point (15 h). (C). GBM cells showed higher intrinsic directionality (accumulated/net distance) when cultured in a 3D Col-HA matrix. Data...
Data
Presence of astrocytes increases 2D GBM cell migration while presence of astrocyte conditioned media (ACM) only increases migration of GBM10 but not GBM43. (A). Accumulated distance of migration during 15 h. (B). Net migration distance between initial (0 h) and final points of migration (15 h). (C). Directionality of migration (net over accumulated...
Article
Full-text available
A key feature of prostate cancer progression is the induction and activation of survival proteins, including the Inhibitor of Apoptosis (IAP) family member survivin. Apurinic/apyrimidinic endonuclease 1/redox effector factor 1 (APE1/Ref-1) is a multifunctional protein that is essential in activating oncogenic transcription factors. Because APE1/Ref...
Article
Full-text available
Reduction-oxidation factor 1-apurinic/apyrimidinic endonuclease (Ref-1/APE1) is a critical node in tumor cells, both as a redox regulator of transcription factor activation and as part of the DNA damage response. As a redox signaling protein, Ref-1/APE1 enhances the transcriptional activity of STAT3, HIF-1α, nuclear factor kappa B, and other transc...
Data
Table S2. Complete results of IPA Pathway analysis.
Article
Full-text available
Pancreatic ductal adenocarcinoma (PDAC) presents at metastatic stage in over 50% of patients. With a survival rate of just 2.7% for patients presenting with distant disease, it is imperative to uncover novel mechanisms capable of suppressing metastasis in PDAC. Previously, we reported that the loss of metastasis suppressor protein 1 (MTSS1) in PDAC...
Article
Full-text available
Apurinic/apyrimidinic endonuclease 1/redox factor-1 (APE1/Ref-1 or APE1) is a multifunctional protein that regulates numerous transcription factors associated with cancer-related pathways. Because APE1 is essential for cell viability, generation of APE1 knockout cell lines and determining a comprehensive list of genes regulated by APE1 has not been...
Article
Background: Drug screening is a key component for drug development and optimizing anti-tumor therapies. Traditionally, in vitro drug testing has been conducted in monolayer systems that are not capable of recapitulating the tumor complexity. Recently, the field has witnessed the rise of interest in 3D culture systems which are capable of reproducin...