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Computational Immune Monitoring Reveals Abnormal Double-Negative T Cells Present across Human Tumor Types.
Greenplate AR, McClanahan DD, Oberholtzer BK, Doxie DB, Roe CE, Diggins KE, Leelatian N, Rasmussen ML, Kelley MC, Gama V, Siska PJ, Rathmell JC, Ferrell PB, Johnson DB, Irish JM
(2019) Cancer Immunol Res 7: 86-99
MeSH Terms: Adenoids, Adult, Aged, Antibodies, Monoclonal, Humanized, Antineoplastic Agents, Immunological, Female, Humans, Imidazoles, MAP Kinase Kinase Kinases, Male, Middle Aged, Monitoring, Immunologic, Neoplasms, Oximes, Palatine Tonsil, Proto-Oncogene Proteins B-raf, Pyridones, Pyrimidinones, T-Lymphocytes
Show Abstract · Added November 11, 2018
Advances in single-cell biology have enabled measurements of >40 protein features on millions of immune cells within clinical samples. However, the data analysis steps following cell population identification are susceptible to bias, time-consuming, and challenging to compare across studies. Here, an ensemble of unsupervised tools was developed to evaluate four essential types of immune cell information, incorporate changes over time, and address diverse immune monitoring challenges. The four complementary properties characterized were (i) systemic plasticity, (ii) change in population abundance, (iii) change in signature population features, and (iv) novelty of cellular phenotype. Three systems immune monitoring studies were selected to challenge this ensemble approach. In serial biopsies of melanoma tumors undergoing targeted therapy, the ensemble approach revealed enrichment of double-negative (DN) T cells. Melanoma tumor-resident DN T cells were abnormal and phenotypically distinct from those found in nonmalignant lymphoid tissues, but similar to those found in glioblastoma and renal cell carcinoma. Overall, ensemble systems immune monitoring provided a robust, quantitative view of changes in both the system and cell subsets, allowed for transparent review by human experts, and revealed abnormal immune cells present across multiple human tumor types.
©2018 American Association for Cancer Research.
3 Communities
1 Members
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19 MeSH Terms
BRAF and MEK inhibitor therapy eliminates Nestin-expressing melanoma cells in human tumors.
Doxie DB, Greenplate AR, Gandelman JS, Diggins KE, Roe CE, Dahlman KB, Sosman JA, Kelley MC, Irish JM
(2018) Pigment Cell Melanoma Res 31: 708-719
MeSH Terms: Antibodies, Neoplasm, Cell Line, Tumor, Humans, Imidazoles, Melanoma, Mitogen-Activated Protein Kinase Kinases, Nestin, Oximes, Phenotype, Protein Kinase Inhibitors, Proto-Oncogene Proteins B-raf, Pyridones, Pyrimidinones
Show Abstract · Added May 21, 2018
Little is known about the in vivo impacts of targeted therapy on melanoma cell abundance and protein expression. Here, 21 antibodies were added to an established melanoma mass cytometry panel to measure 32 cellular features, distinguish malignant cells, and characterize dabrafenib and trametinib responses in BRAF melanoma. Tumor cells were biopsied before neoadjuvant therapy and compared to cells surgically resected from the same site after 4 weeks of therapy. Approximately 50,000 cells per tumor were characterized by mass cytometry and computational tools t-SNE/viSNE, FlowSOM, and MEM. The resulting single-cell view of melanoma treatment response revealed initially heterogeneous melanoma tumors were consistently cleared of Nestin-expressing melanoma cells. Melanoma cell subsets that persisted to week 4 were heterogeneous but expressed SOX2 or SOX10 proteins and specifically lacked surface expression of MHC I proteins by MEM analysis. Traditional histology imaging of tissue microarrays from the same tumors confirmed mass cytometry results, including persistence of NES- SOX10+ S100β+ melanoma cells. This quantitative single-cell view of melanoma treatment response revealed protein features of malignant cells that are not eliminated by targeted therapy.
© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
2 Communities
1 Members
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13 MeSH Terms
A Nonquiescent "Idling" Population State in Drug-Treated, BRAF-Mutated Melanoma.
Paudel BB, Harris LA, Hardeman KN, Abugable AA, Hayford CE, Tyson DR, Quaranta V
(2018) Biophys J 114: 1499-1511
MeSH Terms: Cell Line, Tumor, Drug Resistance, Neoplasm, Epigenesis, Genetic, Humans, Melanoma, Molecular Targeted Therapy, Mutation, Proto-Oncogene Proteins B-raf
Show Abstract · Added April 15, 2018
Targeted therapy is an effective standard of care in BRAF-mutated malignant melanoma. However, the duration of tumor remission varies unpredictably among patients, and relapse is almost inevitable. Here, we examine the responses of several BRAF-mutated melanoma cell lines (including isogenic subclones) to BRAF inhibitors. We observe complex response dynamics across cell lines, with short-term responses (<100 h) varying from cell line to cell line. In the long term, however, we observe equilibration of all drug-treated populations into a nonquiescent state characterized by a balanced rate of death and division, which we term the "idling" state, and to our knowledge, this state has not been previously reported. Using mathematical modeling, we propose that the observed population-level dynamics are the result of cells transitioning between basins of attraction within a drug-modified phenotypic landscape. Each basin is associated with a drug-induced proliferation rate, a recently introduced metric of an antiproliferative drug effect. The idling population state represents a new dynamic equilibrium in which cells are distributed across the landscape such that the population achieves zero net growth. By fitting our model to experimental drug-response data, we infer the phenotypic landscapes of all considered melanoma cell lines and provide a unifying view of how BRAF-mutated melanomas respond to BRAF inhibition. We hypothesize that the residual disease observed in patients after targeted therapy is composed of a significant number of idling cells. Thus, defining molecular determinants of the phenotypic landscape that idling populations occupy may lead to "targeted landscaping" therapies based on rational modification of the landscape to favor basins with greater drug susceptibility.
Copyright © 2018 Biophysical Society. Published by Elsevier Inc. All rights reserved.
0 Communities
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8 MeSH Terms
Frequent BRAF mutations suggest a novel oncogenic driver in colonic neuroendocrine carcinoma.
Idrees K, Padmanabhan C, Liu E, Guo Y, Gonzalez RS, Berlin J, Dahlman KB, Beauchamp RD, Shi C
(2018) J Surg Oncol 117: 284-289
MeSH Terms: Adult, Aged, Biomarkers, Tumor, Carcinogenesis, Case-Control Studies, Colonic Neoplasms, DNA Mutational Analysis, DNA, Neoplasm, Female, Follow-Up Studies, Humans, Male, Middle Aged, Mutation, Neuroendocrine Tumors, Prognosis, Proto-Oncogene Proteins B-raf
Show Abstract · Added March 14, 2018
BACKGROUND AND OBJECTIVES - The World Health Organization (WHO) 2010 has classified GI neuroendocrine neoplasms into neuroendocrine tumor (NET) and high-grade neuroendocrine carcinoma (NEC). The genetic underpinnings of NEC are poorly understood. The aim of the study was to perform genomic profiling of NEC to better characterize this aggressive disease.
METHODS - We identified nine patients with colonic NEC between January 1, 2005 and June 30, 2013. Whole exome sequencing (WES) was performed on tumor DNA from two patients with ≥80% tumor cellularity and matched normal tissue available. Focused BRAF mutational analysis was performed on an additional seven patients via sanger sequencing of BRAF exons 11 and 15.
RESULTS - We identified BRAF exon 15 mutations (c.A1781G: p.D594G and c.T1799A: p.V600E) by WES in two patients. Upon additional screening of seven colonic NECs for BRAF exon 11 and 15 mutations, we identified BRAF V600E mutations in two of seven specimens (29%). Overall, BRAF exon 15 mutations were present in four of nine colonic NECs.
CONCLUSION - Colonic NEC is a rare but aggressive tumor with high frequency (44%) of BRAF mutations. Further investigation is warranted to ascertain the incidence of BRAF mutations in a larger population as BRAF inhibition may be a potential avenue of targeted treatment for these patients.
© 2017 Wiley Periodicals, Inc.
0 Communities
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17 MeSH Terms
Dependence On Glycolysis Sensitizes BRAF-mutated Melanomas For Increased Response To Targeted BRAF Inhibition.
Hardeman KN, Peng C, Paudel BB, Meyer CT, Luong T, Tyson DR, Young JD, Quaranta V, Fessel JP
(2017) Sci Rep 7: 42604
MeSH Terms: Antineoplastic Agents, Cell Line, Tumor, Drug Resistance, Neoplasm, Glucose, Glycolysis, Humans, Indoles, Melanoma, Molecular Targeted Therapy, Mutation, Oncogenes, Pharmacogenomic Variants, Phenotype, Protein Kinase Inhibitors, Proto-Oncogene Proteins B-raf, Sulfonamides, Treatment Outcome
Show Abstract · Added April 18, 2017
Dysregulated metabolism can broadly affect therapy resistance by influencing compensatory signaling and expanding proliferation. Given many BRAF-mutated melanoma patients experience disease progression with targeted BRAF inhibitors, we hypothesized therapeutic response is related to tumor metabolic phenotype, and that altering tumor metabolism could change therapeutic outcome. We demonstrated the proliferative kinetics of BRAF-mutated melanoma cells treated with the BRAF inhibitor PLX4720 fall along a spectrum of sensitivity, providing a model system to study the interplay of metabolism and drug sensitivity. We discovered an inverse relationship between glucose availability and sensitivity to BRAF inhibition through characterization of metabolic phenotypes using nearly a dozen metabolic parameters in Principle Component Analysis. Subsequently, we generated rho0 variants that lacked functional mitochondrial respiration and increased glycolytic metabolism. The rho0 cell lines exhibited increased sensitivity to PLX4720 compared to the respiration-competent parental lines. Finally, we utilized the FDA-approved antiretroviral drug zalcitabine to suppress mitochondrial respiration and to force glycolysis in our cell line panel, resulting in increased PLX4720 sensitivity via shifts in EC50 and Hill slope metrics. Our data suggest that forcing tumor glycolysis in melanoma using zalcitabine or other similar approaches may be an adjunct to increase the efficacy of targeted BRAF therapy.
1 Communities
4 Members
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17 MeSH Terms
Non-Invasive Glutamine PET Reflects Pharmacological Inhibition of BRAF In Vivo.
Schulte ML, Hight MR, Ayers GD, Liu Q, Shyr Y, Washington MK, Manning HC
(2017) Mol Imaging Biol 19: 421-428
MeSH Terms: Amino Acid Transport System ASC, Animals, Cell Line, Tumor, Colonic Neoplasms, Female, Glutamine, Humans, Liver Neoplasms, Mice, Nude, Minor Histocompatibility Antigens, Mutation, Positron-Emission Tomography, Protein Kinase Inhibitors, Proto-Oncogene Proteins B-raf, Xenograft Model Antitumor Assays
Show Abstract · Added April 6, 2017
PURPOSE - This study aimed to study whether cancer cells possess distinguishing metabolic features compared with surrounding normal cells, such as increased glutamine uptake. Given this, quantitative measures of glutamine uptake may reflect critical processes in oncology. Approximately, 10 % of patients with colorectal cancer (CRC) express BRAF , which may be actionable with selective BRAF inhibitors or in combination with inhibitors of complementary signaling axes. Non-invasive and quantitative predictive measures of response to these targeted therapies remain poorly developed in this setting. The primary objective of this study was to explore 4-[F]fluoroglutamine (4-[F]F-GLN) positron emission tomography (PET) to predict response to BRAF-targeted therapy in preclinical models of colon cancer.
PROCEDURES - Tumor microarrays from patients with primary human colon cancers (n = 115) and CRC liver metastases (n = 111) were used to evaluate the prevalence of ASCT2, the primary glutamine transporter in oncology, by immunohistochemistry. Subsequently, 4-[F]F-GLN PET was evaluated in mouse models of human BRAF -expressing and BRAF wild-type CRC.
RESULTS - Approximately 70 % of primary colon cancers and 53 % of metastases exhibited positive ASCT2 immunoreactivity, suggesting that [F]4-F-GLN PET could be applicable to a majority of patients with colon cancer. ASCT2 expression was not associated selectively with the expression of mutant BRAF. Decreased 4-[F]F-GLN predicted pharmacological response to single-agent BRAF and combination BRAF and PI3K/mTOR inhibition in BRAF -mutant Colo-205 tumors. In contrast, a similar decrease was not observed in BRAF wild-type HCT-116 tumors, a setting where BRAF-targeted therapies are ineffective.
CONCLUSIONS - 4-[F]F-GLN PET selectively reflected pharmacodynamic response to BRAF inhibition when compared with 2-deoxy-2[F]fluoro-D-glucose PET, which was decreased non-specifically for all treated cohorts, regardless of downstream pathway inhibition. These findings illustrate the utility of non-invasive PET imaging measures of glutamine uptake to selectively predict response to BRAF-targeted therapy in colon cancer and may suggest further opportunities to inform colon cancer clinical trials using targeted therapies against MAPK activation.
0 Communities
2 Members
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15 MeSH Terms
Oncogenic KRAS and BRAF Drive Metabolic Reprogramming in Colorectal Cancer.
Hutton JE, Wang X, Zimmerman LJ, Slebos RJ, Trenary IA, Young JD, Li M, Liebler DC
(2016) Mol Cell Proteomics 15: 2924-38
MeSH Terms: Biosynthetic Pathways, Cell Line, Tumor, Colorectal Neoplasms, Gene Expression Regulation, Neoplastic, Glucose, Humans, Lactic Acid, Mutation, Proteomics, Proto-Oncogene Proteins B-raf, ras Proteins
Show Abstract · Added April 27, 2017
Metabolic reprogramming, in which altered utilization of glucose and glutamine supports rapid growth, is a hallmark of most cancers. Mutations in the oncogenes KRAS and BRAF drive metabolic reprogramming through enhanced glucose uptake, but the broader impact of these mutations on pathways of carbon metabolism is unknown. Global shotgun proteomic analysis of isogenic DLD-1 and RKO colon cancer cell lines expressing mutant and wild type KRAS or BRAF, respectively, failed to identify significant differences (at least 2-fold) in metabolic protein abundance. However, a multiplexed parallel reaction monitoring (PRM) strategy targeting 73 metabolic proteins identified significant protein abundance increases of 1.25-twofold in glycolysis, the nonoxidative pentose phosphate pathway, glutamine metabolism, and the phosphoserine biosynthetic pathway in cells with KRAS G13D mutations or BRAF V600E mutations. These alterations corresponded to mutant KRAS and BRAF-dependent increases in glucose uptake and lactate production. Metabolic reprogramming and glucose conversion to lactate in RKO cells were proportional to levels of BRAF V600E protein. In DLD-1 cells, these effects were independent of the ratio of KRAS G13D to KRAS wild type protein. A study of 8 KRAS wild type and 8 KRAS mutant human colon tumors confirmed the association of increased expression of glycolytic and glutamine metabolic proteins with KRAS mutant status. Metabolic reprogramming is driven largely by modest (<2-fold) alterations in protein expression, which are not readily detected by the global profiling methods most commonly employed in proteomic studies. The results indicate the superiority of more precise, multiplexed, pathway-targeted analyses to study functional proteome systems. Data are available through MassIVE Accession MSV000079486 at ftp://MSV000079486@massive.ucsd.edu.
© 2016 by The American Society for Biochemistry and Molecular Biology, Inc.
0 Communities
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11 MeSH Terms
Using avatars to win the fight over BRAF inhibitor resistance.
Vilgelm AE, Richmond A
(2016) Pigment Cell Melanoma Res 29: 398-9
MeSH Terms: Cell Line, Tumor, Drug Resistance, Neoplasm, Humans, Indoles, Melanoma, Protein Kinase Inhibitors, Proto-Oncogene Proteins B-raf, Sulfonamides
Added April 18, 2017
1 Communities
2 Members
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8 MeSH Terms
Guiding Oncology Patients Through the Maze of Precision Medicine.
Giuse NB, Kusnoor SV, Koonce TY, Naylor HM, Chen SC, Blasingame MN, Anderson IA, Micheel CM, Levy MA, Ye F, Lovly CM
(2016) J Health Commun 21 Suppl 1: 5-17
MeSH Terms: Adult, Aged, Caregivers, Decision Support Systems, Clinical, Female, Follow-Up Studies, Health Knowledge, Attitudes, Practice, Health Literacy, Humans, Male, Melanoma, Middle Aged, Mutation, Patient Education as Topic, Precision Medicine, Proto-Oncogene Proteins B-raf
Show Abstract · Added April 17, 2019
As the role of genomics in health care grows, patients increasingly require adequate genetic literacy to fully engage in their care. This study investigated a model for delivering consumer-friendly genetic information to improve understanding of precision medicine using health literacy and learning style principles. My Cancer Genome (MCG), a freely available cancer decision support tool, was used as a testbed. MCG content on a melanoma tumor mutation, BRAF V600E, was translated to a 6th-grade reading level, incorporating multiple learning modalities. A total of 90 patients and caregivers were recruited from a melanoma clinic at an academic medical center and randomized to 3 groups. Group A (control) received an exact copy of text from MCG. Group B was given the same content with hyperlinks to videos explaining key genetic concepts, identified and labeled by the team as knowledge pearls. Group C received the translated content with the knowledge pearls embedded. Changes in knowledge were measured through pre and post questionnaires. Group C showed the greatest improvement in knowledge. The study results demonstrate that providing information based on health literacy and learning style principles can improve patients' understanding of genetic concepts, thus increasing their likelihood of taking an active role in any decision making concerning their health.
0 Communities
1 Members
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MeSH Terms
Fibroblast-Mediated Collagen Remodeling Within the Tumor Microenvironment Facilitates Progression of Thyroid Cancers Driven by BrafV600E and Pten Loss.
Jolly LA, Novitskiy S, Owens P, Massoll N, Cheng N, Fang W, Moses HL, Franco AT
(2016) Cancer Res 76: 1804-13
MeSH Terms: Cell Proliferation, Collagen, Fibroblasts, Humans, PTEN Phosphohydrolase, Proto-Oncogene Proteins B-raf, Thyroid Neoplasms, Tumor Microenvironment
Show Abstract · Added February 5, 2016
Contributions of the tumor microenvironment (TME) to progression in thyroid cancer are largely unexplored and may illuminate a basis for understanding rarer aggressive cases of this disease. In this study, we investigated the relationship between the TME and thyroid cancer progression in a mouse model where thyroid-specific expression of oncogenic BRAF and loss of Pten (Braf(V600E)/Pten(-/-)/TPO-Cre) leads to papillary thyroid cancers (PTC) that rapidly progress to poorly differentiated thyroid cancer (PDTC). We found that fibroblasts were recruited to the TME of Braf(V600E)/Pten(-/-)/TPO-Cre thyroid tumors. Conditioned media from cell lines established from these tumors, but not tumors driven by mutant H-ras, induced fibroblast migration and proliferation in vitro Notably, the extracellular matrix of Braf(V600E)/Pten(-/-)/TPO-Cre tumors was enriched with stromal-derived fibrillar collagen, compared with wild-type or Hras-driven tumors. Further, type I collagen enhanced the motility of Braf(V600E)/Pten(-/-)/TPO-Cre tumor cells in vitro In clinical specimens, we found COL1A1 and LOX to be upregulated in PTC and expressed at highest levels in PDTC and anaplastic thyroid cancer. Additionally, increased expression levels of COL1A1 and LOX were associated with decreased survival in thyroid cancer patients. Overall, our results identified fibroblast recruitment and remodeling of the extracellular matrix as pivotal features of the TME in promoting thyroid cancer progression, illuminating candidate therapeutic targets and biomarkers in advanced forms of this malignancy. Cancer Res; 76(7); 1804-13. ©2016 AACR.
©2016 American Association for Cancer Research.
1 Communities
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8 MeSH Terms