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Rxivist combines preprints from bioRxiv with data from Twitter to help you find the papers being discussed in your field. Currently indexing 83,751 bioRxiv papers from 360,722 authors.

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in category cancer biology

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121: The NetrinG1/NGL-1 Axis promotes pancreatic tumorigenesis through cancer associated fibroblast driven nutritional support and immunosuppression
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Posted to bioRxiv 25 May 2018

The NetrinG1/NGL-1 Axis promotes pancreatic tumorigenesis through cancer associated fibroblast driven nutritional support and immunosuppression
1,581 downloads cancer biology

Ralph Francescone, Débora Barbosa Vendramini-Costa, Janusz Franco-Barraza, Jessica Wagner, Alexander Muir, Allison N. Lau, Linara Gabitova, Tatiana Pazina, Sapna Gupta, Tiffany Luong, Neelima Shah, Dustin Rollins, Ruchi Malik, Roshan Thapa, Diana Restifo, Yan Zhou, Kathy Q Cai, Harvey H Hensley, Yinfei Tan, Warren D Kruger, Karthik Devarajan, Siddharth Balachandran, Andres J Klein-Szanto, Wafik S. El-Deiry, Matthew G. Vander Heiden, Suraj Peri, Kerry S. Campbell, Igor Astsaturov, Edna Cukierman

Pancreatic ductal adenocarcinoma (PDAC) has a poor 5-year survival rate and lacks effective therapeutics. Therefore, it is of paramount importance to identify new targets. Using multi-plex data from patient tissue, three-dimensional co-culturing in vitro assays, and orthotopic murine models, we identified Netrin G1 (NetG1) and Netrin G1 ligand (NGL-1) as promoters of PDAC tumorigenesis. NetG1+ cancer-associated fibroblasts (CAFs) supported PDAC survival, through a NetG1/NGL-1 mediated effect on glutamate/glutamine metabolism. NetG1+ CAFs were intrinsically immunosuppressive and inhibited NK cell mediated killing of tumor cells. These functions were partially mediated by vesicular glutamate transporter 1 and glutamine synthetase. This study uncovered an important link between CAF driven metabolism and its immunosuppressive capacity, suggesting NetG1 and NGL-1 as potential targets in PDAC. Significance PDAC is a devastating disease lacking effective therapies. A major hallmark of PDAC is desmoplasia, characterized by the expansion of CAFs and their extracellular matrix, creating a unique microenvironment that limits blood-supplied nutrition and is highly immunosuppressive. A better understanding of the role of CAFs in PDAC may lead to the identification of new targets for therapeutic intervention. Here, we uncovered two potential targets, NetG1 in CAFs and its binding partner NGL-1 in tumor cells. NetG1 in CAFs was important for the metabolic support of PDAC cells and for the intrinsic immunosuppressive capacity of CAFs, while NGL-1 in PDAC cells drove tumorigenesis. Our results helped clarify the role that CAFs play in PDAC, by defining CAF phenotypes through NetG1 expression. Finally, we established a link between CAF driven metabolism and their intrinsic immunosuppressive capacity. Thus, NetG1/NGL-1 axis mediates cell reciprocal and cell autonomous functions in PDAC, representing new attractive targets for this aggressive disease.

122: Single-chromosome aneuploidy commonly functions as a tumor suppressor
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Posted to bioRxiv 19 Feb 2016

Single-chromosome aneuploidy commonly functions as a tumor suppressor
1,578 downloads cancer biology

Jason M. Sheltzer, Julie H. Ko, Nicole C. Habibe Burgos, Erica S. Chung, Colleen M. Meehl, Verena Passerini, Zuzana Storchova, Angelika Amon

Whole-chromosome aneuploidy is a hallmark of human malignancies. The prevalence of chromosome segregation errors in cancer - first noted more than 100 years ago - has led to the widespread belief that aneuploidy plays a crucial role in tumor development. Here, we set out to test this hypothesis. We transduced congenic euploid and trisomic fibroblasts with 14 different oncogenes or oncogene combinations, thereby creating genetically-matched cancer cell lines that differ only in karyotype. Surprisingly, nearly all aneuploid cell lines divided slowly in vitro, formed few colonies in soft agar, and grew poorly as xenografts, relative to matched euploid lines. Similar results were obtained when comparing a near-diploid human colorectal cancer cell line with derivatives of that line that harbored extra chromosomes. Only a few aneuploid lines grew at close to wild-type levels, and no aneuploid line exhibited greater tumorigenic capabilities than its euploid counterpart. These results demonstrate that rather than promoting tumorigenesis, aneuploidy, particularly single chromosome gains, can very often function as a tumor suppressor. Moreover, our results suggest one potential way that cancers can overcome the tumor suppressive effects of aneuploidy: rapidly-growing aneuploid cell lines that had evolved in vitro or in vivo demonstrated recurrent karyotype changes that were absent from their euploid counterparts. Thus, the genome-destabilizing effects of single-chromosome aneuploidy may facilitate the development of balanced, high-complexity karyotypes that are frequently found in advanced malignancies.

123: Single-Cell Transcriptome Analysis of Lineage Diversity and Microenvironment in High-Grade Glioma
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Posted to bioRxiv 19 Jan 2018

Single-Cell Transcriptome Analysis of Lineage Diversity and Microenvironment in High-Grade Glioma
1,571 downloads cancer biology

Jinzhou Yuan, Hanna Mendes Levitin, Veronique Frattini, Erin C. Bush, Deborah M. Boyett, Jorge Samanamud, Michele Ceccarelli, Athanassios Dovas, George Zanazzi, Peter Canoll, Jeffrey N. Bruce, Anna Lasorella, Antonio Iavarone, Peter A. Sims

Despite extensive molecular characterization, we lack a comprehensive understanding of lineage identity, differentiation, and proliferation in high-grade gliomas (HGGs). We sampled the cellular milieu of HGGs with massively-parallel single-cell RNA-Seq. While HGG cells can resemble glia or even immature neurons and form branched lineage structures, mesenchymal transformation results in unstructured populations. Glioma cells in a subset of mesenchymal tumors lose their neural lineage identity, express inflammatory genes, and co-exist with marked myeloid infiltration, reminiscent of molecular interactions between glioma and immune cells established in animal models. Additionally, we discovered a tight coupling between lineage resemblance and proliferation among malignantly transformed cells. Glioma cells that resemble oligodendrocyte progenitors, which proliferate in the brain, are often found in the cell cycle. Conversely, glioma cells that resemble astrocytes, neuroblasts, and oligodendrocytes, which are non-proliferative in the brain, are generally non-cycling in tumors. These studies reveal a relationship between cellular identity and proliferation in HGG and distinct population structures that reflects the extent of neural and non-neural lineage resemblance among malignantly transformed cells.

124: The genomic landscape of metastatic castration-resistant prostate cancers reveals multiple distinct genotypes with potential clinical impact
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Posted to bioRxiv 11 Feb 2019

The genomic landscape of metastatic castration-resistant prostate cancers reveals multiple distinct genotypes with potential clinical impact
1,564 downloads cancer biology

Lisanne F. van Dessel, Job van Riet, Minke Smits, Yanyun Zhu, Paul Hamberg, Michiel S. van der Heijden, Andries M. Bergman, Inge M. van Oort, Ronald de Wit, Emile E. Voest, Neeltje Steeghs, Takafumi N. Yamaguchi, Julie Livingstone, Paul C. Boutros, John W.M. Martens, Stefan Sleijfer, Edwin Cuppen, Wilbert Zwart, Harmen J.G. van de Werken, Niven Mehra, Martijn P. Lolkema

Metastatic castration-resistant prostate cancer (mCRPC) has a highly complex genomic landscape. With the recent development of novel treatments, accurate stratification strategies are needed. Here we present the whole-genome sequencing (WGS) analysis of fresh-frozen metastatic biopsies from 197 mCRPC patients. Using unsupervised clustering based on genomic features, we define eight distinct genomic clusters. We observe potentially clinically relevant genotypes, including microsatellite instability (MSI), homologous recombination deficiency (HRD) enriched with genomic deletions and BRCA2 aberrations, a tandem duplication genotype associated with CDK12-/- and a chromothripsis-enriched subgroup. Our data suggests that stratification on WGS characteristics may improve identification of MSI, CDK12-/- and HRD patients. From WGS and ChIP-seq data, we show the potential relevance of recurrent alterations in non-coding regions identified with WGS and highlight the central role of AR signaling in tumor progression. These data underline the potential value of using WGS to accurately stratify mCRPC patients into clinically actionable subgroups.

125: TET2 binding to enhancers facilitates transcription factor recruitment in hematopoietic cells
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Posted to bioRxiv 31 May 2018

TET2 binding to enhancers facilitates transcription factor recruitment in hematopoietic cells
1,553 downloads cancer biology

Kasper D. Rasmussen, Ivan Berest, Sandra Kessler, Koutarou Nishimura, Lucía Simón-Carrasco, George S Vassilou, Marianne T Pedersen, Jesper Christensen, Judith B Zaugg, Kristian Helin

The epigenetic regulator TET2 is frequently mutated in hematological diseases. Mutations have been shown to arise in hematopoietic stem cells early in disease development, lead to altered DNA methylation landscapes and to an increased risk of hematopoietic malignancy. Here, we show by genome-wide mapping of TET2 binding sites in different cell types that TET2 localizes to regions of open chromatin and cell-type specific enhancers. We find that deletion of Tet2 in native hematopoiesis as well as fully transformed Acute Myeloid Leukemia (AML) results in changes in transcription factor (TF) activity within these regions, and we demonstrate that loss of TET2 leads to enzymatic activity-dependent attenuation of chromatin binding of the hematopoietic TF CDX4. Together, these findings demonstrate that TET2 activity shapes the local chromatin environment at enhancers to facilitate TF binding and provide a compelling example of how epigenetic dysregulation can affect gene expression patterns and drive disease development.

126: YAP1 oncogene is a context-specific driver for pancreatic ductal adenocarcinoma
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Posted to bioRxiv 23 Feb 2018

YAP1 oncogene is a context-specific driver for pancreatic ductal adenocarcinoma
1,552 downloads cancer biology

Bo Tu, Jun Yao, Sammy Ferri-Borgogno, Jun Zhao, Shujuan Chen, Qiuyun Wang, Liang Yan, Xin Zhou, Cihui Zhu, Seungmin Bang, Qing Chang, Christopher A. Bristow, Ya’an Kang, Hongwu Zheng, Huamin Wang, Jason B. Fleming, Michael Kim, Timothy P. Heffernan, Giulio F. Draetta, Duojia Pan, Anirban Maitra, Wantong Yao, Sonal Gupta, Haoqiang Ying

Transcriptomic profiling classifies pancreatic ductal adenocarcinoma (PDAC) into several molecular subtypes with distinctive histological and clinical characteristics. However, little is known about the molecular mechanisms that define each subtype and their correlation with clinical outcome. Mutant KRAS is the most prominent driver in PDAC, present in over 90% of tumors, but the dependence of tumors on oncogenic KRAS signaling varies between subtypes. In particular, squamous subtype are relatively independent of oncogenic KRAS signaling and typically display much more aggressive clinical behavior versus progenitor subtype. Here, we identified that YAP1 activation is enriched in the squamous subtype and associated with poor prognosis. Activation of YAP1 in progenitor subtype cancer cells profoundly enhanced malignant phenotypes and transformed progenitor subtype cells into squamous subtype. Conversely, depletion of YAP1 specifically suppressed tumorigenicity of squamous subtype PDAC cells. Mechanistically, we uncovered a significant positive correlation between WNT5A expression and the YAP1 activity in human PDAC, and demonstrated that WNT5A overexpression led to YAP1 activation and recapitulated YAP1-dependent but Kras-independent phenotype of tumor progression and maintenance. Thus, our study identifies YAP1 oncogene as a major driver of squamous subtype PDAC and uncovers the role of WNT5A in driving PDAC malignancy through activation of the YAP pathway.

127: Comprehensive characterization of pediatric AML reveals diverse fusion oncoproteins and age-specific mutational interactions
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Posted to bioRxiv 13 Jun 2017

Comprehensive characterization of pediatric AML reveals diverse fusion oncoproteins and age-specific mutational interactions
1,533 downloads cancer biology

Hamid Bolouri, Jason E. Farrar, Timothy Triche, Rhonda E. Ries, Emilia L. Lim, Todd A. Alonzo, Yussanne Ma, Richard Moore, Andrew J. Mungall, Marco A. Marra, Jinghui Zhang, Xiaotu Ma, Yu Liu, Yanling Liu, Jaime M. Guidry Auvil, Tanja M. Davidsen, Patee Gesuwan, Leandro C. Hermida, Bodour Salhia, Stephen Capone, Giridharan Ramsingh, Christian Michel Zwaan, Sanne Noort, Stephen R. Piccolo, E. Anders Kolb, Alan S. Gamis, Malcolm A. Smith, Daniela S. Gerhard, Soheil Meshinchi

We present the molecular landscape of pediatric acute myeloid leukemia (AML), characterizing nearly 1,000 participants in Childrens Oncology Group (COG) AML trials. The COG/NCI TARGET AML initiative assessed cases by whole-genome, targeted DNA, mRNA, miRNA sequencing and CpG methylation profiling. Validated DNA variants revealed diverse, infrequent mutations with fewer than 40 genes mutated in >2% of cases. In contrast, somatic structural variants, including novel gene fusions and focal MBNL1, ZEB2, and ELF1 deletions, were disproportionately prevalent in young as compared to adult patients. Conversely, DNMT3A and TP53 mutations, common in adults, are conspicuously absent from virtually all pediatric cases. Novel GATA2, FLT3, and CBL mutations, recurrent MYC-ITD, NRAS, KRAS, and WT1 mutations are frequent in pediatric AML. Deletions, mutations, and promoter DNA hypermethylation convergently impact Wnt signaling, Polycomb repression, innate immune cell interactions, and a cluster of zinc finger genes associated with KMT2A rearrangements. These results highlight the need for, and facilitate the development of, age-tailored targeted therapies for the treatment of pediatric AML.

128: Both Fallopian Tube and Ovarian Surface Epithelium Can Act as Cell-of-Origin for High Grade Serous Ovarian Carcinoma
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Posted to bioRxiv 29 Nov 2018

Both Fallopian Tube and Ovarian Surface Epithelium Can Act as Cell-of-Origin for High Grade Serous Ovarian Carcinoma
1,529 downloads cancer biology

Shuang Zhang, Tao Zhang, Igor Dolgalev, Hao Ran, Douglas A. Levine, Benjamin G Neel

The cell of origin of high grade serous ovarian carcinoma (HGSOC) remains controversial, with fallopian tube epithelium FTE and ovarian surface epithelium (OSE) each suggested as candidates. Here, by using genetically engineered mouse models and novel organoid systems, we assessed the tumor forming capacity and properties of FTE and OSE harboring the same oncogenic abnormalities. Combined RB family inactivation (via T121 expression) and Tp53 mutation in Pax8+ FTE caused transformation to Serous Tubal Intraepithelial Carcinoma (STIC), which rapidly metastasized to the ovarian surface. This mouse model was recapitulated by FTE organoids, which, upon orthotopic injection, generated widely metastatic HGSOC. The same genetic lesions in Lgr5+ OSE cells or organoids also caused metastatic HGSOC, although with longer latency and lower penetrance. Comparative transcriptome analysis was consistent with different human HGSOCs arising from FTE and OSE. Furthermore, FTE- and OSE-derived organoids showed differential sensitivity to HGSOC chemotherapeutics. Our results comport with a dualistic origin for HGSOC and suggest the cell-of-origin could influence therapeutic response.

129: METABOLIC DIVERSITY IN HUMAN NON-SMALL CELL LUNG CANCER CELLS
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Posted to bioRxiv 11 Mar 2019

METABOLIC DIVERSITY IN HUMAN NON-SMALL CELL LUNG CANCER CELLS
1,529 downloads cancer biology

Pei-Hsuan Chen, Ling Cai, Kenneth Huffman, Chendong Yang, Jiyeon Kim, Brandon Faubert, Lindsey Boroughs, Bookyung Ko, Jessica Sudderth, Elizabeth A McMillan, Luc Girard, Michael Peyton, Misty D Shields, David Shames, Hyun Seok Kim, Brenda Timmons, Ikuo Sekine, Rebecca Britt, Stephanie Weber, Lauren A Byers, John V Heymach, Michael A. White, John D. Minna, Guanghua Xiao, Ralph J. DeBerardinis

Intermediary metabolism in cancer cells is regulated by diverse cell-autonomous processes including signal transduction and gene expression patterns arising from specific oncogenotypes and cell lineages. Although it is well established that metabolic reprogramming is a hallmark of cancer, we lack a full view of the diversity of metabolic programs in cancer cells and an unbiased assessment of the associations between metabolic pathway preferences and other cell-autonomous processes. Here we quantified over 100 metabolic features, mostly from 13C enrichment of molecules from central carbon metabolism, in over 80 non-small cell lung cancer (NSCLC) cell lines cultured under identical conditions. Because these cell lines were extensively annotated for oncogenotype, gene expression, protein expression and therapeutic sensitivity, the resulting database enables the user to uncover new relationships between metabolism and these orthogonal processes.

130: Novel insights into the molecular heterogeneity of hepatocellular carcinoma
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Posted to bioRxiv 19 Jan 2017

Novel insights into the molecular heterogeneity of hepatocellular carcinoma
1,527 downloads cancer biology

Juan Jovel, Zhen Lin, Sandra O’keefe, Steven Willows, Weiwei Wang, Guangzhi Zhang, Jordan Patterson, David J. Kelvin, Gane Ka-Shu Wong, Andrew L Mason

Hepatocellular carcinoma (HCC) is influenced by numerous factors, which results in diverse genetic, epigenetic and transcriptional scenarios, thus posing obvious challenges for disease management. We scrutinized the molecular heterogeneity of HCC with a multi-omics approach in two small cohorts of resected and explanted livers. Whole-genome transcriptomics was conducted, including polyadenylated transcripts and micro (mi)-RNAs. Copy number variants (CNV) were inferred from whole genome low-pass sequencing data. Fifty-six cancer-related genes were screened using an oncology panel assay. HCC was associated with a dramatic transcriptional deregulation of hundreds of protein-coding genes suggesting downregulation of drugs catabolism, induction of inflammatory responses, and increased cell proliferation in resected livers. Moreover, several long non-coding RNAs and miRNAs not reported previously in the context of HCC were found deregulated. In explanted livers, downregulation of genes involved in energy-producing processes and upregulation of genes aiding in glycolysis were detected. Numerous CNV events were observed, with conspicuous hotspots on chromosomes 1 and 17. Amplifications were more common than deletions, and spanned regions containing genes potentially involved in tumorigenesis. CSF1R, FGFR3, FLT3, NPM1, PDGFRA, PTEN, SMO and TP53 were mutated in all tumors, while other 26 cancer-related genes were mutated with variable penetrance. Our results highlight a remarkable molecular heterogeneity between HCC tumors and reinforce the notion that precision medicine approaches are urgently needed for cancer treatment. We expect that our results will serve as a valuable dataset that will generate hypotheses for us or other researchers to evaluate to ultimately improve our understanding of HCC biology.

131: Dynamic 3D chromosomal landscapes in acute leukemia
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Posted to bioRxiv 04 Aug 2019

Dynamic 3D chromosomal landscapes in acute leukemia
1,521 downloads cancer biology

Andreas Kloetgen, Palaniraja Thandapani, Panagiotis Ntziachristos, Yohana Ghebrechristos, Sofia Nomikou, Charalampos Lazaris, Xufeng Chen, Hai Hu, Sofia Bakogianni, Jingjing Wang, Yi Fu, Francesco Boccalatte, Hua Zhong, Elisabeth Paietta, Thomas Trimarchi, Yixing Zhu, Pieter van Vlierberghe, Giorgio G Inghirami, Timothee Lionnet, Iannis Aifantis, Aristotelis Tsirigos

Three-dimensional (3D) chromatin architectural changes can alter the integrity of topologically associated domains (TADs) and rewire specific enhancer-promoter interactions impacting gene expression. Recently, such alterations have been implicated in human disease, highlighting the need for a deeper understanding of their role. Here, we investigate the reorganization of chromatin architecture in T cell acute lymphoblastic leukemia (T-ALL) using primary human leukemia specimens and its dynamic responses to pharmacological agents. Systematic integration of matched in situ Hi-C, RNA-Seq and CTCF ChIP-Seq datasets revealed widespread changes in intra-TAD chromatin interactions and TAD boundary insulation in T-ALL. Our studies identify and focus on a TAD "fusion" event being associated with loss of CTCF-mediated insulation, enabling direct interactions between the MYC promoter and a distal super-enhancer. Moreover, our data show that small molecule inhibitors targeting either oncogenic signal transduction or epigenetic regulation reduce specific 3D interactions associated with transformation. Overall, our study highlights the impact, complexity and dynamic nature of 3D chromatin architecture in human acute leukemia.

132: The dynamics of ERK signaling in melanoma, and the response to BRAF or MEK inhibition, are cell cycle dependent.
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Posted to bioRxiv 23 Apr 2018

The dynamics of ERK signaling in melanoma, and the response to BRAF or MEK inhibition, are cell cycle dependent.
1,520 downloads cancer biology

Chloe M. Simpson, Nicola Ferrari, Fernando Calvo, Chris Bakal

Activating BRAF mutations are thought to drive melanoma tumorigenesis and metastasis by constitutively activating MEK and ERK. Small molecule inhibitors (SMIs) of BRAF or MEK have shown promise as melanoma therapeutics. However, the development of resistance to these inhibitors in both the short- and long-term is common; warranting investigation into how these SMIs influence ERK signaling dynamics. Quantitative single cell imaging of ERK activity in living cells reveals both intra- and inter-cell heterogeneity in this activity in isogenic melanoma populations harboring a BRAFV600E mutation. This heterogeneity is largely due to a cell-cycle dependent bifurcation of ERK activity. Moreover, we show there are also cell-cycle dependent responses in ERK activity following BRAF or MEK inhibition. Prior to, but not following, CDK4/6-mediated passage through the Restriction Point (RP) ERK activity is sensitive to BRAF and MEK inhibitors. In contrast, for cells that have passed the RP, ERK activity will remain elevated even in the presence of BRAF or MEK inhibition until mitosis. Our results show that ERK activity - even in the presence of activating BRAF mutations - is regulated by both positive and negative feedback loops that are engaged in cell-cycle dependent fashions. CDK4/6 inhibition sensitizes ERK activity to BRAF or MEK inhibition by preventing passage the transition from a BRAF/MEK dependent to independent state. Our results have implications for the use of MEK and BRAF inhibitors as melanoma therapeutics, and offer a rational basis for the use of these inhibitors in combination with CDK4/6 inhibition during cancer therapy.

133: Identification and characterization of long non-coding RNAs as targets of mammary tumor cell proliferation and migration
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Posted to bioRxiv 11 Jan 2016

Identification and characterization of long non-coding RNAs as targets of mammary tumor cell proliferation and migration
1,514 downloads cancer biology

Sarah D Diermeier, Kung-Chi Chang, Susan M Freier, Junyan Song, Alexander Krasnitz, Frank Rigo, C. Frank Bennett, David Spector

Recent genome-wide studies revealed that as much as 80% of the human genome can be transcribed whereas only 2% of this RNA is translated into proteins. Non-coding transcripts can be subdivided into several groups, with long non-coding RNAs (lncRNAs) representing the largest and most diverse class. With breast cancer being the most frequent malignancy in women worldwide, we set out to investigate the potential of lncRNAs as novel therapeutic targets. By performing RNA-Seq on tumor sections and mammary organoids from MMTVPyMT and MMTV-Neu-NDL mice, modeling the luminal B and HER2/neuamplified subtypes of human breast cancer respectively, we generated a comprehensive catalog of differentially expressed lncRNAs. We identified several hundred potentially oncogenic lncRNAs that were over-expressed in a subtype specific manner as well as numerous lncRNAs up-regulated in both models. Among these lncRNA we defined a subset of 30 previously uncharacterized lncRNAs as Mammary Tumor Associated RNAs (MaTARs) and we identified human orthologs. We functionally validated the role of these MaTARs by antisense oligonucleotide (ASO) mediated knockdown in primary mammary tumor cells and 3D ex vivo organoids. Upon independent knockdown of 15 MaTARs, we observed significantly reduced cell proliferation, invasion and/or collective cell migration in a cancer-specific context. Thus, MaTARs are likely key drivers of mammary tumor progression and/or metastasis and represent promising new therapeutic targets.

134: The interface of malignant and immunologic clonal dynamics in high-grade serous ovarian cancer
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Posted to bioRxiv 04 Oct 2017

The interface of malignant and immunologic clonal dynamics in high-grade serous ovarian cancer
1,510 downloads cancer biology

Allen W. Zhang, Andrew McPherson, Katy Milne, David R. Kroeger, Phineas T Hamilton, Alex Miranda, Tyler Funnell, Sonya Laan, Dawn R. Cochrane, Jamie LP Lim, Winnie Yang, Andrew Roth, Maia A. Smith, Camila de Souza, Julie Ho, Kane Tse, Thomas Zeng, Inna Shlafman, Michael R. Mayo, Richard Moore, Henrik Failmezger, Andreas Heindl, Yi Kan Wang, Ali Bashashati, Scott D. Brown, Daniel Lai, Adrian N. C. Wan, Cydney B. Nielsen, Alexandre Bouchard-Côté, Yinyin Yuan, Wyeth W. Wasserman, C. Blake Gilks, Anthony N. Karnezis, Samuel Aparicio, Jessica N. McAlpine, David G. Huntsman, Robert A Holt, Brad H Nelson, Sohrab P. Shah

High-grade serous ovarian cancer exhibits extensive intratumoral heterogeneity coupled with widespread intraperitoneal disease. Despite this, metastatic spread of tumor clones is non-random, implying the existence of local microenvironmental factors that shape tumor progression. We interrogated the molecular interface between tumor-infiltrating lymphocytes (TIL) and cancer cells in 143 samples from 21 patients using whole-genome sequencing, immunohistochemistry, histologic image analysis, gene expression profiling, and T- and B-cell receptor sequencing. We identify 3 immunologic response categories, which frequently co-exist within individual patients. Furthermore, epithelial CD8+ TIL were inversely associated with malignant cell diversity, evidenced by subclonal neoepitope elimination and spatial tracking between tumor and T-cell clones. Intersecting mutational signatures and immune analysis showed that foldback inversion genomic aberrations lead to worse outcomes even in the presence of cytotoxic TIL (n=433). Thus, regional variation in immune contexture mirrors the pattern of intraperitoneal malignant spread, provoking new perspectives for treatment of this challenging disease.

135: Toxicity Management in CAR T cell therapy for B-ALL: Mathematical modelling as a new avenue for improvement.
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Posted to bioRxiv 22 Apr 2016

Toxicity Management in CAR T cell therapy for B-ALL: Mathematical modelling as a new avenue for improvement.
1,503 downloads cancer biology

Shalla Hanson, David Robert Grimes, Jake P. Taylor-King, Benedikt Bauer, Pravnam I. Warman, Ziv Frankenstein, Artem Kaznatcheev, Michael J. Bonassar, Vincent L. Cannataro, Zeinab Y. Motawe, Ernesto A. B. F. Lima, Sungjune Kim, Marco L. Davila, Arturo Araujo

Advances in genetic engineering have made it possible to reprogram individual immune cells to express receptors that recognise markers on tumour cell surfaces. The process of re-engineering T cell lymphocytes to express Chimeric Antigen Receptors (CARs), and then re-infusing the CAR-modified T cells into patients to treat various cancers is referred to as CAR T cell therapy. This therapy is being explored in clinical trials - most prominently for B Cell Acute Lymphoblastic Leukaemia (B-ALL), a common B cell malignancy, for which CAR T cell therapy has led to remission in up to 90% of patients. Despite this extraordinary response rate, however, potentially fatal inflammatory side effects occur in up to 10% of patients who have positive responses. Further, approximately 50% of patients who initially respond to the therapy relapse. Significant improvement is thus necessary before the therapy can be made widely available for use in the clinic. To inform future development, we develop a mathematical model to explore interactions between CAR T cells, inflammatory toxicity, and individual patients' tumour burdens in silico. This paper outlines the underlying system of coupled ordinary differential equations designed based on well-known immunological principles and widely accepted views on the mechanism of toxicity development in CAR T cell therapy for B-ALL - and reports in silico outcomes in relationship to standard and recently conjectured predictors of toxicity in a heterogeneous, randomly generated patient population. Our initial results and analyses are consistent with and connect immunological mechanisms to the clinically observed, counterintuitive hypothesis that initial tumour burden is a stronger predictor of toxicity than is the dose of CAR T cells administered to patients. We outline how the mechanism of action in CAR T cell therapy can give rise to such non-standard trends in toxicity development, and demonstrate the utility of mathematical modelling in understanding the relationship between predictors of toxicity, mechanism of action, and patient outcomes.

136: Predicting master transcription factors from pan-cancer expression data
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Posted to bioRxiv 12 Nov 2019

Predicting master transcription factors from pan-cancer expression data
1,502 downloads cancer biology

Jessica Reddy, Marcos A. S. Fonseca, Rosario I. Corona, Robbin Nameki, Felipe Segato Dezem, Isaac A. Klein, Heidi Chang, Daniele Chaves-Moreira, Lena Afeyan, Tathiane M Malta, Xianzhi Lin, Forough Abbasi, Alba Font-Tello, Thais Sabedot, Paloma Cejas, Norma Rodríguez-Malavé, Ji-Heui Seo, De-Chen Lin, Ursula Matulonis, Beth Y Karlan, Simon A Gayther, Alexander Gusev, Houtan Noushmehr, Henry Long, Matthew L Freedman, Ronny Drapkin, Brian J Abraham, Richard A. Young, Kate Lawrenson

The function of critical developmental regulators can be subverted by cancer cells to control expression of oncogenic transcriptional programs. These "master transcription factors" (MTFs) are often essential for cancer cell survival and represent vulnerabilities that can be exploited therapeutically. The current approaches to identify candidate MTFs examine super-enhancer associated transcription factor-encoding genes with high connectivity in network models. This relies on chromatin immunoprecipitation-sequencing (ChIP-seq) data, which is technically challenging to obtain from primary tumors, and is currently unavailable for many cancer types and clinically relevant subtypes. In contrast, gene expression data are more widely available, especially for rare tumors and subtypes where MTFs have yet to be discovered. We have developed a predictive algorithm called CaCTS (Cancer Core Transcription factor Specificity) to identify candidate MTFs using pan-cancer RNA-sequencing data from The Cancer Genome Atlas. The algorithm identified 273 candidate MTFs across 34 tumor types and recovered known tumor MTFs. We also made novel predictions, including for cancer types and subtypes for which MTFs have not yet been characterized. Clustering based on MTF predictions reproduced anatomic groupings of tumors that share 1-2 lineage-specific candidates, but also dictated functional groupings, such as a squamous group that comprised five tumor subtypes sharing 3 common MTFs. PAX8, SOX17, and MECOM were candidate factors in high-grade serous ovarian cancer (HGSOC), an aggressive tumor type where the core regulatory circuit is currently uncharacterized. PAX8, SOX17, and MECOM are required for cell viability and lie proximal to super-enhancers in HGSOC cells. ChIP-seq revealed that these factors co-occupy HGSOC regulatory elements globally and co-bind at critical gene loci including MUC16 (CA-125). Addiction to these factors was confirmed in studies using THZ1 to inhibit transcription in HGSOC cells, suggesting early down-regulation of these genes may be responsible for cytotoxic effects of THZ1 on HGSOC models. Identification of MTFs across 34 tumor types and 140 subtypes, especially for those with limited understanding of transcriptional drivers paves the way to therapeutic targeting of MTFs in a broad spectrum of cancers.

137: Chromatin mapping and single-cell immune profiling define the temporal dynamics of ibrutinib drug response in chronic lymphocytic leukemia
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Posted to bioRxiv 03 Apr 2019

Chromatin mapping and single-cell immune profiling define the temporal dynamics of ibrutinib drug response in chronic lymphocytic leukemia
1,501 downloads cancer biology

André F. Rendeiro, Thomas Krausgruber, Nikolaus Fortelny, Fangwen Zhao, Thomas Penz, Matthias Farlik, Linda C Schuster, Amelie Nemc, Szabolcs Tasnády, Marienn Réti, Zoltán Mátrai, Donat Alpar, Csaba Bödör, Christian Schmidl, Christoph Bock

Chronic lymphocytic leukemia (CLL) is a genetically, epigenetically, and clinically heterogeneous disease. Despite this heterogeneity, the Bruton tyrosine kinase (BTK) inhibitor ibrutinib provides effective treatment for the vast majority of CLL patients. To define the underlining regulatory program, we analyzed high-resolution time courses of ibrutinib treatment in closely monitored patients, combining cellular phenotyping (flow cytometry), single-cell transcriptome profiling (scRNA-seq), and chromatin mapping (ATAC-seq). We identified a consistent regulatory program shared across all patients, which was further validated by an independent CLL cohort. In CLL cells, this program starts with a sharp decrease of NF-κB binding, followed by reduced regulatory activity of lineage-defining transcription factors (including PAX5 and IRF4) and erosion of CLL cell identity, finally leading to the acquisition of a quiescence-like gene signature which was shared across several immune cell types. Nevertheless, we observed patient-to-patient variation in the speed of its execution, which we exploited to predict patient-specific dynamics in the response to ibrutinib based on pre-treatment samples. In aggregate, our study describes the cellular, molecular, and regulatory effects of therapeutic B cell receptor inhibition in CLL at high temporal resolution, and it establishes a broadly applicable method for epigenome/transcriptome-based treatment monitoring.

138: Comparison of 3.0 T PAC versus 1.5 T ERC MRI in Detecting Local Prostate Carcinoma.
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Posted to bioRxiv 09 Jun 2016

Comparison of 3.0 T PAC versus 1.5 T ERC MRI in Detecting Local Prostate Carcinoma.
1,499 downloads cancer biology

Xin Ye, Udochukwu yoyo, Albert Lu, Jed Dixon, Heather Rojas, Samuel Randolph, Thomas Kelly

Increased utilization of prostate-specific antigen screening and prostate imaging has led to detection of smaller indolent tumors that traditional brachytherapy and prostectomy may be too aggressive for. New targeted techniques require greater locational accuracy of tumor detection to guide treatment. Prostate MRIs can be important for initial staging and for guiding targeted biopsies and treatments. We compared the accuracy of local staging of prostate cancer using 1.5 Tesla MRI with endorectal coil (ERC) versus 3 Tesla MRI with pelvic array coil (PAC) to the gold standard of trans-rectal US guided biopsies (TRUS). ERC is uncomfortable and has many imaging artifacts that may limit detection, so we hypothesize that 3 T MRI with PAC will have improved performance. 72 patients underwent prostate MRIs and TRUS prostate biopsies from 2008-2011 (33 were excluded due to prior radiation therapy, 24 patients underwent 1.5 T ERC and 15 underwent 3.0 T PAC.) 3.0 T PAC was trending towards greater sensitivity although we lack the statistical power for significance.

139: Cellular transformation by combined lineage conversion and oncogene expression
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Posted to bioRxiv 22 Jan 2019

Cellular transformation by combined lineage conversion and oncogene expression
1,484 downloads cancer biology

Biswajyoti Sahu, Paivi Pihlajamaa, Kaiyang Zhang, Kimmo Palin, Saija Ahonen, Alejandra Cervera, Ari Ristimaki, Lauri Aaltonen, Sampsa Hautaniemi, Jussi Taipale

Cancer is the most complex genetic disease known, with mutations implicated in more than 250 genes. However, it is still elusive which specific mutations found in human patients lead to tumorigenesis. Here we show that a combination of oncogenes that is characteristic of liver cancer (CTNNB1, TERT, MYC) induces senescence in human fibroblasts and primary hepatocytes. However, reprogramming fibroblasts to a liver progenitor fate, induced hepatocytes (iHeps), makes them sensitive to transformation by the same oncogenes. The transformed iHeps are highly proliferative, tumorigenic in nude mice, and bear gene expression signatures of liver cancer. These results show that tumorigenesis is triggered by a combination of three elements: the set of driver mutations, the cellular lineage, and the state of differentiation of the cells along the lineage. Our results provide direct support for the role of cell identity as a key determinant in transformation, and establish a paradigm for studying the dynamic role of oncogenic drivers in human tumorigenesis. ### Competing Interest Statement The authors have declared no competing interest.

140: Higher gene expression variability in the more aggressive subtype of chronic lymphocytic leukemia
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Posted to bioRxiv 29 May 2014

Higher gene expression variability in the more aggressive subtype of chronic lymphocytic leukemia
1,476 downloads cancer biology

Simone Ecker, Vera Pancaldi, Daniel Rico, Alfonso Valencia

Background: Chronic Lymphocytic Leukemia (CLL) presents two subtypes which have drastically different clinical outcomes. So far, these two subtypes are not associated to clear differences in gene expression profiles. Interestingly, recent results have highlighted important roles for heterogeneity, both at the genetic and at the epigenetic level in CLL progression. Results: We propose to use gene expression variability across patients to investigate differences between the two CLL subtypes. We find that the most aggressive type of this disease shows higher variability of gene expression across patients and we elaborate on this observation to produce a method that classifies patients into clinical subtypes. Finally, we find that, overall, genes that show higher variability in the aggressive subtype are related to cell cycle, development and inter-cellular communication, probably related to faster progression of this disease subtype. Conclusions: There are strong relations between disease subtype and gene expression variability linking significantly increased expression variability to phenotypes such as aggressiveness and resistance to therapy in CLL.

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