A5034535391- Advanced Breast Cancer Therapies
- Pancreatic and Hepatic Oncology Research
- Cancer-related Molecular Pathways
- Cancer Immunotherapy and Biomarkers
- Cancer Genomics and Diagnostics
- Epigenetics and DNA Methylation
- HER2/EGFR in Cancer Research
- Colorectal Cancer Treatments and Studies
- Nanoplatforms for cancer theranostics
- Breast Cancer Treatment Studies
- Cancer Cells and Metastasis
- Caveolin-1 and cellular processes
- Cancer, Hypoxia, and Metabolism
- Advanced Nanomaterials in Catalysis
- RNA modifications and cancer
- Lung Cancer Research Studies
- Cytokine Signaling Pathways and Interactions
- Estrogen and related hormone effects
- CAR-T cell therapy research
- Cancer-related gene regulation
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Neuroendocrine Tumor Research Advances
- Metabolism, Diabetes, and Cancer
- Microtubule and mitosis dynamics
- Cell Adhesion Molecules Research
Roswell Park Comprehensive Cancer Center
2018-2025
Advanced Tissue (United States)
2023
Cancer Genetics (United States)
2021-2022
The University of Texas Southwestern Medical Center
2012-2021
Harold C. Simmons Comprehensive Cancer Center
2014-2021
University of Arizona
2016-2018
University of Arizona Cancer Center
2016-2018
Southwestern Medical Center
2014-2017
Vanderbilt University Medical Center
2017
Simmons University
2014-2015
Here, we propose a new model for understanding the Warburg effect in tumor metabolism. Our hypothesis is that epithelial cancer cells induce (aerobic glycolysis) neighboring stromal fibroblasts. These cancer-associated fibroblasts, then undergo myo-fibroblastic differentiation, and secrete lactate pyruvate (energy metabolites resulting from aerobic glycolysis). Epithelial could take up these energy-rich use them mitochondrial TCA cycle, thereby promoting efficient energy production (ATP...
Abstract Pancreatic ductal adenocarcinoma (PDA) has a dismal prognosis and insights into both disease etiology targeted intervention are needed. A total of 109 micro-dissected PDA cases were subjected to whole-exome sequencing. Microdissection enriches tumour cellularity enhances mutation calling. Here we show that environmental stress alterations in DNA repair genes associate with distinct spectra. Copy number target multiple suppressive/oncogenic loci; however, amplification MYC is...
Loss of stromal fibroblast caveolin-1 (Cav-1) is a powerful single independent predictor poor prognosis in human breast cancer patients, and associated with early tumor recurrence, lymph node metastasis, tamoxifen-resistance. We developed novel co-culture system to understand the mechanism(s) by which loss Cav-1 induces "lethal micro-environment". Here, we propose new paradigm explain prognostic value Cav-1. In this model, cells induce oxidative stress fibroblasts, then acts as "metabolic"...
Significance MicroRNAs (miRNAs) are small ∼22-nt RNAs that important regulators of posttranscriptional gene expression. Since their initial discovery, they have been shown to be involved in many cellular processes, and misexpression is associated with disease etiology. Currently, nearly 2,800 human miRNAs annotated public repositories. A key question miRNA research how harbored by the genome. To answer this question, we examined 1,323 short RNA sequence samples identified 3,707 novel miRNAs,...
Recently, using a co-culture system, we demonstrated that MCF7 epithelial cancer cells induce oxidative stress in adjacent cancer-associated fibroblasts, resulting the autophagic/lysosomal degradation of stromal caveolin-1 (Cav-1). However, detailed signaling mechanism(s) underlying this process remain largely unknown. Here, show hypoxia is sufficient to autophagic Cav-1 which blocked by lysosomal inhibitor chloroquine. Concomitant with hypoxia-induced Cav-1, see upregulation number...
Recently, we proposed a new mechanism for understanding the Warburg effect in cancer metabolism. In this paradigm, cancer-associated fibroblasts undergo aerobic glycolysis, and extrude lactate to “feed” adjacent cells, which then drives mitochondrial biogenesis oxidative metabolism cells. Thus, there is vectorial transport of energy-rich substrates from fibroblastic tumor stroma anabolic A prediction hypothesis that should express MCT4, mono-carboxylate transporter has been implicated efflux...
Retinoblastoma (RB; encoded by RB1) is a tumor suppressor that frequently disrupted in tumorigenesis and acts multiple cell types to suppress cycle progression. The role of RB progression, however, poorly defined. Here, we have identified critical for protecting against progression through regulation targets distinct from control. In analyses human prostate cancer samples, loss was infrequently observed primary disease predominantly associated with transition the incurable,...
The majority of estrogen receptor (ER)-positive breast cancers are treated with endocrine therapy. While this is effective, acquired resistance to therapies targeted against ER a major clinical challenge. Here, model systems ER-positive differential susceptibility therapy were employed define common nodes for new therapeutic interventions. These analyses revealed that cell cycle progression effectively uncoupled from the activity and functional state in these models. In context, cyclin D1...
We have recently proposed a new mechanism for explaining energy transfer in cancer metabolism. In this scenario, cells behave as metabolic parasites, by extracting nutrients from normal host cells, such fibroblasts, via the secretion of hydrogen peroxide initial trigger. Oxidative stress tumor microenvironment then leads to autophagy-driven catabolism, mitochondrial dys-function, and aerobic glycolysis. This, turn, produces high-energy (such L-lactate, ketones, glutamine) that drive anabolic...
The mechanisms underlying adaptive resistance of melanoma to targeted therapies remain unclear. By combining ChIP sequencing with microarray-based gene profiling, we determined that ERBB3 is upregulated by FOXD3, a transcription factor promotes RAF inhibitors in melanoma. Enhanced signaling promoted pathway cultured cell lines and mouse xenograft models. was dependent on ERBB2; targeting ERBB2 lapatinib combination the inhibitor PLX4720 reduced tumor burden extended latency regrowth vivo...
We have recently proposed a new model of cancer metabolism to explain the role aerobic glycolysis and L-lactate production in fueling tumor growth metastasis. In this model, cells secrete hydrogen peroxide (H2O2), initiating oxidative stress stroma. This, turn, drives secretion from cancer-associated fibroblasts. Secreted then fuels mitochondrial (OXPHOS) epithelial cells, by acting as paracrine onco-metabolite. previously termed type two-compartment "Reverse Warburg Effect," takes place...
To model the heterogeneity of breast cancer as observed in clinic, we employed an ex vivo tumor tissue. This methodology maintained histological integrity tissue unselected cancers, and importantly, explants retained key molecular markers that are currently used to guide treatment (e.g., ER Her2 status). The primary tumors displayed expected wide range positivity for proliferation marker Ki67, a strong positive correlation between Ki67 indices corresponding explanted tissues was observed....
Acquired resistance to cyclin-dependent kinases 4 and 6 (CDK4/6) small-molecule inhibitors in breast cancer arises through mechanisms that are yet uncharacterized. In this study, we used a kinome-wide siRNA screen identify that, when downregulated, yield sensitivity the CDK4/6 inhibitor ribociclib. manner, identified 3-phosphoinositide-dependent protein kinase 1 (PDK1) as key modifier of ribociclib estrogen receptor-positive MCF-7 cells. Pharmacologic inhibition PDK1 with GSK2334470...
// Jorge Franco 1 , Agnieszka K. Witkiewicz 1,2 and Erik S. Knudsen Department of Pathology UT Southwestern, Dallas TX 2 Simmons Cancer Center, Correspondence: Knudsen, email: Witkiewicz, Keywords : RB, CDK4/6, palbocicllb, pancreatic cancer, E2F Received July 10, 2014 Accepted 26, Published Abstract Pancreatic ductal adenocarcinoma (PDA) has a poor prognosis, in part, due to the therapy-recalcitrant nature disease. Loss CDK4/6 inhibitor CDKN2A is signature genetic event PDA. Therefore, PDA...
The p27 protein is a canonical negative regulator of cell proliferation and acts primarily by inhibiting cyclin-dependent kinases (CDKs). Under some circumstances, associated with active CDK4, but no mechanism for activation has been described. We found that p27, when phosphorylated tyrosine kinases, allosterically activated CDK4 in complex cyclin D1 (CDK4-CycD1). Structural biochemical data revealed binding (phosp27) to altered the kinase adenosine triphosphate site promote phosphorylation...
Due to loss of p16ink4a in pancreatic ductal adenocarcinoma (PDA), pharmacological suppression CDK4/6 could represent a potent target for treatment. In PDA models, inhibition had variable effect on cell cycle but yielded accumulation ATP and mitochondria. Pharmacological inhibitors induce cyclin D1 protein levels; however, RB activation was required sufficient mitochondrial accumulation. stimulated glycolytic oxidative metabolism associated with an increase mTORC1 activity. MTOR MEK potently...
Purpose: Pancreatic ductal adenocarcinoma (PDAC) is associated with an immunosuppressive milieu that supports immune system evasion and disease progression. Here, we interrogated genetic, stromal, immunologic features of PDAC to delineate impact on prognosis means more effectively employ immunotherapy.Experimental Design: A cohort 109 cases annotated for overall survival was utilized as a primary discovery cohort. Gene expression analysis defined subtypes were confirmed in the Cancer Genome...