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Results: 1 to 10 of 45

Publication Record


MYC and MCL1 Cooperatively Promote Chemotherapy-Resistant Breast Cancer Stem Cells via Regulation of Mitochondrial Oxidative Phosphorylation.
Lee KM, Giltnane JM, Balko JM, Schwarz LJ, Guerrero-Zotano AL, Hutchinson KE, Nixon MJ, Estrada MV, Sánchez V, Sanders ME, Lee T, Gómez H, Lluch A, Pérez-Fidalgo JA, Wolf MM, Andrejeva G, Rathmell JC, Fesik SW, Arteaga CL
(2017) Cell Metab 26: 633-647.e7
MeSH Terms: Animals, Cell Line, Tumor, Drug Resistance, Neoplasm, Female, Humans, Mice, Nude, Mitochondria, Myeloid Cell Leukemia Sequence 1 Protein, Neoplastic Stem Cells, Oxidative Phosphorylation, Proto-Oncogene Proteins c-myc, Reactive Oxygen Species, Triple Negative Breast Neoplasms
Show Abstract · Added March 14, 2018
Most patients with advanced triple-negative breast cancer (TNBC) develop drug resistance. MYC and MCL1 are frequently co-amplified in drug-resistant TNBC after neoadjuvant chemotherapy. Herein, we demonstrate that MYC and MCL1 cooperate in the maintenance of chemotherapy-resistant cancer stem cells (CSCs) in TNBC. MYC and MCL1 increased mitochondrial oxidative phosphorylation (mtOXPHOS) and the generation of reactive oxygen species (ROS), processes involved in maintenance of CSCs. A mutant of MCL1 that cannot localize in mitochondria reduced mtOXPHOS, ROS levels, and drug-resistant CSCs without affecting the anti-apoptotic function of MCL1. Increased levels of ROS, a by-product of activated mtOXPHOS, led to the accumulation of HIF-1α. Pharmacological inhibition of HIF-1α attenuated CSC enrichment and tumor initiation in vivo. These data suggest that (1) MYC and MCL1 confer resistance to chemotherapy by expanding CSCs via mtOXPHOS and (2) targeting mitochondrial respiration and HIF-1α may reverse chemotherapy resistance in TNBC.
Copyright © 2017. Published by Elsevier Inc.
0 Communities
1 Members
0 Resources
13 MeSH Terms
Triple-negative breast cancer: challenges and opportunities of a heterogeneous disease.
Bianchini G, Balko JM, Mayer IA, Sanders ME, Gianni L
(2016) Nat Rev Clin Oncol 13: 674-690
MeSH Terms: Androgen Antagonists, BRCA2 Protein, Biomarkers, Tumor, Clinical Trials as Topic, Female, Humans, Immune System, Immunotherapy, Mitogen-Activated Protein Kinases, Molecular Targeted Therapy, Mutation, Neoplastic Stem Cells, Phosphoinositide-3 Kinase Inhibitors, Poly(ADP-ribose) Polymerase Inhibitors, Prognosis, Triple Negative Breast Neoplasms, Ubiquitin-Protein Ligases
Show Abstract · Added April 6, 2017
Chemotherapy is the primary established systemic treatment for patients with triple-negative breast cancer (TNBC) in both the early and advanced-stages of the disease. The lack of targeted therapies and the poor prognosis of patients with TNBC have fostered a major effort to discover actionable molecular targets to treat patients with these tumours. Massively parallel sequencing and other 'omics' technologies have revealed an unexpected level of heterogeneity of TNBCs and have led to the identification of potentially actionable molecular features in some TNBCs, such as germline BRCA1/2 mutations or 'BRCAness', the presence of the androgen receptor, and several rare genomic alterations. Whether these alterations are molecular 'drivers', however, has not been clearly established. A subgroup of TNBCs shows a high degree of tumour-infiltrating lymphocytes that also correlates with a lower risk of disease relapse and a higher likelihood of benefit from chemotherapy. Proof-of-principle studies with immune-checkpoint inhibitors in advanced-stage TNBC have yielded promising results, indicating the potential benefit of immunotherapy for patients with TNBC. In this Review, we discuss the most relevant molecular findings in TNBC from the past decade and the most promising therapeutic opportunities derived from these data.
0 Communities
1 Members
0 Resources
17 MeSH Terms
Advanced Intestinal Cancers often Maintain a Multi-Ancestral Architecture.
Zahm CD, Szulczewski JM, Leystra AA, Paul Olson TJ, Clipson L, Albrecht DM, Middlebrooks M, Thliveris AT, Matkowskyj KA, Washington MK, Newton MA, Eliceiri KW, Halberg RB
(2016) PLoS One 11: e0150170
MeSH Terms: Adenocarcinoma, Adenoma, Animals, Carcinoma in Situ, Cell Lineage, Cell Transformation, Neoplastic, Clone Cells, Disease Models, Animal, Disease Progression, Evolution, Molecular, Fatty Acid-Binding Proteins, Female, Gene Expression Regulation, Neoplastic, Genes, APC, Genes, Reporter, Integrases, Intestinal Mucosa, Intestinal Neoplasms, Luminescent Proteins, Male, Mice, Mice, Inbred C57BL, Models, Biological, Mosaicism, Neoplasm Invasiveness, Neoplastic Stem Cells, RNA, Untranslated, Rats, Transgenes, Tumor Microenvironment
Show Abstract · Added April 12, 2016
A widely accepted paradigm in the field of cancer biology is that solid tumors are uni-ancestral being derived from a single founder and its descendants. However, data have been steadily accruing that indicate early tumors in mice and humans can have a multi-ancestral origin in which an initiated primogenitor facilitates the transformation of neighboring co-genitors. We developed a new mouse model that permits the determination of clonal architecture of intestinal tumors in vivo and ex vivo, have validated this model, and then used it to assess the clonal architecture of adenomas, intramucosal carcinomas, and invasive adenocarcinomas of the intestine. The percentage of multi-ancestral tumors did not significantly change as tumors progressed from adenomas with low-grade dysplasia [40/65 (62%)], to adenomas with high-grade dysplasia [21/37 (57%)], to intramucosal carcinomas [10/23 (43%]), to invasive adenocarcinomas [13/19 (68%)], indicating that the clone arising from the primogenitor continues to coexist with clones arising from co-genitors. Moreover, neoplastic cells from distinct clones within a multi-ancestral adenocarcinoma have even been observed to simultaneously invade into the underlying musculature [2/15 (13%)]. Thus, intratumoral heterogeneity arising early in tumor formation persists throughout tumorigenesis.
0 Communities
1 Members
0 Resources
30 MeSH Terms
Treatment of Triple-Negative Breast Cancer with TORC1/2 Inhibitors Sustains a Drug-Resistant and Notch-Dependent Cancer Stem Cell Population.
Bhola NE, Jansen VM, Koch JP, Li H, Formisano L, Williams JA, Grandis JR, Arteaga CL
(2016) Cancer Res 76: 440-52
MeSH Terms: Cell Line, Tumor, Drug Resistance, Neoplasm, Humans, Mechanistic Target of Rapamycin Complex 2, Multiprotein Complexes, Neoplastic Stem Cells, Signal Transduction, TOR Serine-Threonine Kinases, Triple Negative Breast Neoplasms, Xenograft Model Antitumor Assays
Show Abstract · Added March 10, 2016
Approximately 30% of triple-negative breast cancers (TNBC) harbor molecular alterations in PI3K/mTOR signaling, but therapeutic inhibition of this pathway has not been effective. We hypothesized that intrinsic resistance to TORC1/2 inhibition is driven by cancer stem cell (CSC)-like populations that could be targeted to enhance the antitumor action of these drugs. Therefore, we investigated the molecular mechanisms by which PI3K/mTOR inhibitors affect the stem-like properties of TNBC cells. Treatment of established TNBC cell lines with a PI3K/mTOR inhibitor or a TORC1/2 inhibitor increased the expression of CSC markers and mammosphere formation. A CSC-specific PCR array revealed that inhibition of TORC1/2 increased FGF1 and Notch1 expression. Notch1 activity was also induced in TNBC cells treated with TORC1/2 inhibitors and associated with increased mitochondrial metabolism and FGFR1 signaling. Notably, genetic and pharmacologic blockade of Notch1 abrogated the increase in CSC markers, mammosphere formation, and in vivo tumor-initiating capacity induced by TORC1/2 inhibition. These results suggest that targeting the FGFR-mitochondrial metabolism-Notch1 axis prevents resistance to TORC1/2 inhibitors by eradicating drug-resistant CSCs in TNBC, and may thus represent an attractive therapeutic strategy to improve drug responsiveness and efficacy.
©2015 American Association for Cancer Research.
0 Communities
1 Members
0 Resources
10 MeSH Terms
Expression of CD24, a Stem Cell Marker, in Pancreatic and Small Intestinal Neuroendocrine Tumors.
Salaria S, Means A, Revetta F, Idrees K, Liu E, Shi C
(2015) Am J Clin Pathol 144: 642-8
MeSH Terms: Biomarkers, Tumor, CD24 Antigen, Humans, Immunohistochemistry, Intestinal Neoplasms, Neoplastic Stem Cells, Neuroendocrine Tumors, Pancreatic Neoplasms
Show Abstract · Added October 8, 2015
OBJECTIVES - CD24 has been considered a normal and cancer stem cell marker. Potential intestinal stem cells weakly express CD24. In the pancreas, CD24 is a possible cancer stem cell marker for ductal adenocarcinoma.
METHODS - Expression of CD24 in intestinal and pancreatic neuroendocrine tumors (NETs) was examined. Immunohistochemistry was performed on benign duodenum, ileum mucosa, and pancreas, as well as primary duodenal, primary and metastatic ileal, and pancreatic NETs.
RESULTS - Scattered CD24-positive cells were noted in the duodenal and ileal crypts, most of which showed a strong subnuclear labeling pattern. Similar expression was observed in 41 (95%) of 43 primary ileal NETs but in only four (15%) of 26 duodenal NETs (P < .01). In addition, metastatic ileal NETs retained CD24 expression. Pancreatic islets did not express CD24, and only rare cells had subnuclear labeling of CD24 in the pancreatic ducts. Unlike ileal NETs, only five (5%) of 92 pancreatic NETs expressed CD24 in the subnuclear compartment (P < .01). All five NETs showed a unique morphology with prominent stromal fibrosis.
CONCLUSIONS - CD24 expression was frequent in primary and metastatic midgut NETs but rare in pancreatic and duodenal NETs. Expression of CD24 in ileal NETs may have future diagnostic and therapeutic implications.
Copyright© by the American Society for Clinical Pathology.
0 Communities
2 Members
0 Resources
8 MeSH Terms
Selenoprotein P influences colitis-induced tumorigenesis by mediating stemness and oxidative damage.
Barrett CW, Reddy VK, Short SP, Motley AK, Lintel MK, Bradley AM, Freeman T, Vallance J, Ning W, Parang B, Poindexter SV, Fingleton B, Chen X, Washington MK, Wilson KT, Shroyer NF, Hill KE, Burk RF, Williams CS
(2015) J Clin Invest 125: 2646-60
MeSH Terms: Animals, Antioxidants, Apoptosis, Colitis, Colonic Neoplasms, DNA Damage, Genomic Instability, Haploinsufficiency, Macrophages, Mice, Mice, Inbred C57BL, Mice, Knockout, Mutagenesis, Site-Directed, Neoplastic Stem Cells, Oxidative Stress, Protein Structure, Tertiary, Selenium, Selenoprotein P, Tumor Microenvironment, Tumor Suppressor Proteins
Show Abstract · Added July 10, 2015
Patients with inflammatory bowel disease are at increased risk for colon cancer due to augmented oxidative stress. These patients also have compromised antioxidant defenses as the result of nutritional deficiencies. The micronutrient selenium is essential for selenoprotein production and is transported from the liver to target tissues via selenoprotein P (SEPP1). Target tissues also produce SEPP1, which is thought to possess an endogenous antioxidant function. Here, we have shown that mice with Sepp1 haploinsufficiency or mutations that disrupt either the selenium transport or the enzymatic domain of SEPP1 exhibit increased colitis-associated carcinogenesis as the result of increased genomic instability and promotion of a protumorigenic microenvironment. Reduced SEPP1 function markedly increased M2-polarized macrophages, indicating a role for SEPP1 in macrophage polarization and immune function. Furthermore, compared with partial loss, complete loss of SEPP1 substantially reduced tumor burden, in part due to increased apoptosis. Using intestinal organoid cultures, we found that, compared with those from WT animals, Sepp1-null cultures display increased stem cell characteristics that are coupled with increased ROS production, DNA damage, proliferation, decreased cell survival, and modulation of WNT signaling in response to H2O2-mediated oxidative stress. Together, these data demonstrate that SEPP1 influences inflammatory tumorigenesis by affecting genomic stability, the inflammatory microenvironment, and epithelial stem cell functions.
0 Communities
6 Members
0 Resources
20 MeSH Terms
Ink4a/Arf-Dependent Loss of Parietal Cells Induced by Oxidative Stress Promotes CD44-Dependent Gastric Tumorigenesis.
Seishima R, Wada T, Tsuchihashi K, Okazaki S, Yoshikawa M, Oshima H, Oshima M, Sato T, Hasegawa H, Kitagawa Y, Goldenring JR, Saya H, Nagano O
(2015) Cancer Prev Res (Phila) 8: 492-501
MeSH Terms: ADP-Ribosylation Factor 1, Animals, Cell Transformation, Neoplastic, Cells, Cultured, Cyclin-Dependent Kinase Inhibitor p16, Hyaluronan Receptors, Immunoenzyme Techniques, Metaplasia, Mice, Mice, Knockout, Neoplastic Stem Cells, Oxidative Stress, Parietal Cells, Gastric, Signal Transduction, Stomach Neoplasms, Wnt1 Protein, p38 Mitogen-Activated Protein Kinases
Show Abstract · Added March 28, 2016
Loss of parietal cells initiates the development of spasmolytic polypeptide-expressing metaplasia (SPEM), a precancerous lesion in stomach. CD44 variant (CD44v) that enhances the ability to defend against reactive oxygen species (ROS) in epithelial cells is expressed de novo in SPEM of K19-Wnt1/C2mE mice, a transgenic model of gastric tumorigenesis, and is required for the efficient development of SPEM and gastric tumor in these animals. The role of ROS and its downstream signaling in CD44-dependent gastric tumorigenesis has remained unknown, however. With the use of the K19-Wnt1/C2mE mouse, we now show that parietal cells in the inflamed stomach are highly sensitive to oxidative stress and manifest activation of p38(MAPK) signaling by ROS. Oral treatment with the antioxidant ascorbic acid or genetic ablation of the Ink4a/Arf locus, a major downstream target of ROS-p38(MAPK) signaling, inhibited parietal cell loss and the subsequent gastric tumorigenesis. Our results indicate that signaling activated by oxidative stress in parietal cells plays a key role in CD44-dependent gastric tumorigenesis. .
©2015 American Association for Cancer Research.
0 Communities
1 Members
0 Resources
17 MeSH Terms
Mutations in early follicular lymphoma progenitors are associated with suppressed antigen presentation.
Green MR, Kihira S, Liu CL, Nair RV, Salari R, Gentles AJ, Irish J, Stehr H, Vicente-Dueñas C, Romero-Camarero I, Sanchez-Garcia I, Plevritis SK, Arber DA, Batzoglou S, Levy R, Alizadeh AA
(2015) Proc Natl Acad Sci U S A 112: E1116-25
MeSH Terms: Antigen-Presenting Cells, CREB-Binding Protein, Chromatin, Flow Cytometry, Histocompatibility Antigens Class II, Humans, Lymphoma, Follicular, Mutation, Neoplastic Stem Cells, Polymerase Chain Reaction
Show Abstract · Added April 15, 2015
Follicular lymphoma (FL) is incurable with conventional therapies and has a clinical course typified by multiple relapses after therapy. These tumors are genetically characterized by B-cell leukemia/lymphoma 2 (BCL2) translocation and mutation of genes involved in chromatin modification. By analyzing purified tumor cells, we identified additional novel recurrently mutated genes and confirmed mutations of one or more chromatin modifier genes within 96% of FL tumors and two or more in 76% of tumors. We defined the hierarchy of somatic mutations arising during tumor evolution by analyzing the phylogenetic relationship of somatic mutations across the coding genomes of 59 sequentially acquired biopsies from 22 patients. Among all somatically mutated genes, CREBBP mutations were most significantly enriched within the earliest inferable progenitor. These mutations were associated with a signature of decreased antigen presentation characterized by reduced transcript and protein abundance of MHC class II on tumor B cells, in line with the role of CREBBP in promoting class II transactivator (CIITA)-dependent transcriptional activation of these genes. CREBBP mutant B cells stimulated less proliferation of T cells in vitro compared with wild-type B cells from the same tumor. Transcriptional signatures of tumor-infiltrating T cells were indicative of reduced proliferation, and this corresponded to decreased frequencies of tumor-infiltrating CD4 helper T cells and CD8 memory cytotoxic T cells. These observations therefore implicate CREBBP mutation as an early event in FL evolution that contributes to immune evasion via decreased antigen presentation.
1 Communities
1 Members
0 Resources
10 MeSH Terms
PDGFRB-rearranged T-lymphoblastic leukemia/lymphoma occurring with myeloid neoplasms: the missing link supporting a stem cell origin.
Ondrejka SL, Jegalian AG, Kim AS, Chabot-Richards DS, Giltnane J, Czuchlewski DR, Shetty S, Sekeres MA, Yenamandra A, Head D, Jagasia M, Hsi ED
(2014) Haematologica 99: e148-51
MeSH Terms: Adult, Bone Marrow, Gene Expression, Humans, Karyotype, Leukemia, Myeloid, Male, Middle Aged, Neoplastic Stem Cells, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Receptor, Platelet-Derived Growth Factor beta, Translocation, Genetic
Added January 20, 2015
0 Communities
1 Members
0 Resources
12 MeSH Terms
Inducible loss of one Apc allele in Lrig1-expressing progenitor cells results in multiple distal colonic tumors with features of familial adenomatous polyposis.
Powell AE, Vlacich G, Zhao ZY, McKinley ET, Washington MK, Manning HC, Coffey RJ
(2014) Am J Physiol Gastrointest Liver Physiol 307: G16-23
MeSH Terms: Adenomatous Polyposis Coli, Animals, Cell Transformation, Neoplastic, Colon, Colonoscopy, Disease Models, Animal, Genes, APC, Hypertrophy, Membrane Glycoproteins, Mice, Mice, Transgenic, Neoplastic Stem Cells, Nerve Tissue Proteins, Positron-Emission Tomography, Precancerous Conditions, Retinal Pigment Epithelium, Time Factors
Show Abstract · Added May 20, 2014
Individuals with familial adenomatous polyposis (FAP) harbor a germline mutation in adenomatous polyposis coli (APC). The major clinical manifestation is development of multiple colonic tumors at a young age due to stochastic loss of the remaining APC allele. Extracolonic features, including periampullary tumors, gastric abnormalities, and congenital hypertrophy of the retinal pigment epithelium, may occur. The objective of this study was to develop a mouse model that simulates these features of FAP. We combined our Lrig1-CreERT2/+ mice with Apcfl/+ mice, eliminated one copy of Apc in leucine-rich repeats and immunoglobulin-like domains protein 1 (Lrig1)-positive (Lrig1(+)) progenitor cells with tamoxifen injection, and monitored tumor formation in the colon by colonoscopy and PET. Initial loss of one Apc allele in Lrig1(+) cells results in a predictable pattern of preneoplastic changes, culminating in multiple distal colonic tumors within 50 days of induction, as well as the extracolonic manifestations of FAP mentioned above. We show that tumor formation can be monitored by noninvasive PET imaging. This inducible stem cell-driven model recapitulates features of FAP and offers a tractable platform on which therapeutic interventions can be monitored over time by colonoscopy and noninvasive imaging.
Copyright © 2014 the American Physiological Society.
1 Communities
4 Members
0 Resources
17 MeSH Terms