Rxivist combines preprints from bioRxiv with data from Twitter to help you find the papers being discussed in your field. Currently indexing 67,591 bioRxiv papers from 298,067 authors.
Most downloaded bioRxiv papers, since beginning of last month
in category cancer biology
2,234 results found. For more information, click each entry to expand.
197 downloads cancer biology
Jantzen Sperry, Janel E Le Belle, Michael C Condro, Lea Guo, Daniel Braas, Nathan Vanderveer-Harris, Kristen K.O. Kim, Whitney B Pope, Ajit S. Divakaruni, Albert Lai, Heather Christofk, Harley I Kornblum
Glioblastoma (GBM) metabolism has traditionally been characterized by a dependence on aerobic glycolysis, prompting use of the ketogenic diet as a potential therapy. We observed growth-promoting effects on U87 GBM of both ketone body and fatty acid (FA) supplementation under physiological glucose conditions. An in vivo assessment of the unrestricted ketogenic diet surprisingly resulted in increased tumor growth and decreased animal survival. These effects are abrogated by FAO inhibition using knockdown of carnitine palmitoyltransferase 1 (CPT1). Primary patient GBM cultures revealed significant utilization of FAO regardless of tumorigenic mutational status and decreased proliferation, increased apoptosis, and elevated mitochondrial ROS production with CPT1 inhibition. Metabolomic tracing with 13C-labeled fatty acids showed significant FA utilization within the TCA cycle, indicating that FAO is used for both bioenergetics and production of key intermediates. These data demonstrate important roles for FA and ketone body metabolism that could serve to improve targeted therapies in GBM.
197 downloads cancer biology
To define the global significance of cellular targets oncology drug in cancer, we examined the fitness-dependency - the loss of cancer cell’s viability in the absence of a test gene, of cancer drug targets across human cancer cells in a CRISPR-Cas9 fitness screening dataset, wherein genes were selectively knocked-down before assaying for the fitness-dependency of 7470 genes in 324 cancer cell lines representing 19 cancer-types. We observed that depletion of 35 out of 47 fitness targets of oncology drugs did not result in an otherwise expected loss of cell fitness in appropriate cancer-types for which drugs targeting these molecules were approved. This raises the possibility of undesirable drug-associated off-target effects in such cancers. In addition, our analysis allowed recognition of 41 drug targets as fitness genes in several cancer-types as candidate targets for repurposing approved oncology drugs for cancer-types in which these drugs were not approved. For example, we found widespread upregulation and associated reduction in the duration of overall survival of cancer patients, and fitness-dependency of the components of mevalonate and purine biosynthesis pathways (currently targeted by bisphosphonates, statins and pemetrexed in certain cancers) in breast and other hard-to-treat cancers for which these drugs are not approved. In brief, the present analysis raises caution about the likelihood of off-target and undesirable drug-associated effects of certain oncology drugs in a subset of cancers where intended drug targets are not fitness genes. This also offers a rationale for repurposing a set of approved oncology drugs for cancer-types that have significant fitness-dependency on a set of cellular targets of such approved drugs. Precise This study provides the global significance of cellular targets oncology drugs in maintaining the cellular fitness of cancer-types for which drugs targeting these cellular targets have been approved or not approved across 19 cancer-types.
196 downloads cancer biology
Understanding subclonal architecture and their biological functions poses one of the key challenges to deeply portray and investigative the cause of triple-negative breast cancer (TNBC). Here we combine single-cell and bulk sequencing data to analyze tumor heterogeneity through characterizing subclone compositions and proportions. Based on sing-cell RNA-seq data (GSE118389) we identified five distinct cell subpopulations and characterized their biological functions based on their gene markers. It is worth noting that C1 and C2 relate to immune functions, while C5 relates to programmed cell death. Then based on subclonal basis gene expression matrix, we applied CBS deconvolution algorithm on TCGA tissue RNA-seq data, and found that patients with low and high C1 proportions have different immune microenvironment; and high C5 proportions would led to poor survival outcome, p-value and HR [95%CI] for five years overall survival in TCGA dataset were 0.0326 and 1.664 [1.038-2.667], and in GSE96058 dataset were 0.0158 and 2.557 [1.160-5.636]. Collectively, our analysis reveals the both intra-tumor and inter-tumor heterogeneity and their association with subclonal microenvironment in TNBC (subclone compositions and proportions), and uncovers the organic combination of subclones dictating poor outcomes in this disease.
192 downloads cancer biology
Zainab Jagani, Gregg Chenail, Kay Xiang, Geoffrey Bushold, Hyo-Eun C Bhang, Ailing Li, GiNell Elliott, Jiang Zhu, Anthony Vattay, Tamara Gilbert, Anka Bric, Rie Kikkawa, Valerie Dubost, Remi Terranova, John Cantwell, Catherine Luu, Serena Silver, Matt Shirley, Francois Huet, Rob Maher, John Reece-Hoyes, David Ruddy, Daniel Rakiec, Joshua Korn, Carsten Russ, Vera Ruda, Julia Dooley, Emily Costa, Isabel Park, Henrik Moebitz, Katsumasa Nakajima, Christopher D Adair, Simon Mathieu, Rukundo Ntaganda, Troy Smith, David Farley, Daniel King, Xiaoling Xie, Raviraj Kulathila, Tiancen Hu, Xuewen Pan, Qicheng Ma, Katarina Vulic, Florencia Rago, Scott Clarkson, Robin Ge, Frederic Sigoillot, Gwynn Pardee, Linda Bagdasarian, Margaret McLaughlin, Kristy Haas, Jan Weiler, Steve Kovats, Mariela Jaskelioff, Marie Apolline-Gerard, Johanna Beil, Ulrike Naumann, Pascal Fortin, Frank P Stegmeier, Michael G Acker, Juliet Williams, Matthew Meyer, James E Bradner, Nicholas Keen, William R Sellers, Francesco Hofmann, Jeffrey Engelman, Darrin Stuart, Julien P.N Papillon
Members of the ATP-dependent SWI/SNF chromatin remodeling complexes are among the most frequently mutated genes in cancer, suggesting their dysregulation plays a critical role. The synthetic lethality between SWI/SNF catalytic subunits BRM/SMARCA2 and BRG1/SMARCA4 has instigated great interest in targeting BRM. Here we have performed a critical and in-depth investigation of novel dual inhibitors (BRM011 and BRM014) of BRM and BRG1 in order to validate their utility as chemical probes of SWI/SNF catalytic function, while obtaining insights into the therapeutic potential of SWI/SNF inhibition. In corroboration of on-target activity, we discovered compound resistant mutations through pooled screening of BRM variants in BRG1-mut cancer cells. Strikingly, genome-wide transcriptional and chromatin profiling (ATAC-Seq) provided further evidence of pharmacological perturbation of SWI/SNF chromatin remodeling as BRM011 treatment induced specific changes in chromatin accessibility and gene expression similar to genetic depletion of BRM. Finally, these compounds have the capacity to inhibit the growth of tumor-xenografts, yielding important insights into the feasibility of developing BRM/BRG1 ATPase inhibitors for the treatment of BRG1-mut lung cancers. Overall, our studies not only establish the feasibility of inhibiting SWI/SNF catalytic function, providing a framework for SWI/SNF therapeutic targeting, but have also yielded successful elucidation of small-molecule inhibitors that will be of importance in probing SWI/SNF function in various disease contexts.
191 downloads cancer biology
Yiqing Zhang, William Nock, Meghan Wyse, Zachary Weber, Elizabeth Adams, Sarah Asad, Sinclair Stockard, David Tallman, Eric P Winer, Nancy U Lin, Mathew Cherian, Maryam B. Lustberg, Bhuvaneswari Ramaswamy, Sagar Sardesai, Jeffrey VanDeusen, Nicole Williams, Robert Wesolowski, Daniel G. Stover
Purpose: Metastatic relapse of triple-negative breast cancer (TNBC) within 2 years of diagnosis is associated with particularly aggressive disease and a distinct clinical course relative to TNBCs that relapse beyond 2 years. We hypothesized that rapid relapse TNBCs (rrTNBC; metastatic relapse or death <2 years) reflect unique genomic features relative to late relapse (lrTNBC; >2 years). Patients and Methods: We identified 453 primary TNBCs from three publicly-available datasets and characterized each as rrTNBc, lrTNBC, or 'no relapse' (nrTNBC: no relapse/death with at least 5 years follow-up). We compiled primary tumor clinical and multi-omic data, including transcriptome (n=453), copy number alterations (CNAs; n=317), and mutations in 171 cancer-related genes (n=317), then calculated published gene expression and immune signatures. Results: Patients with rrTNBC were higher stage at diagnosis (Chi-square p<0.0001) while lrTNBC were more likely to be non-basal PAM50 subtype (Chi-square p=0.03). Among 125 expression signatures, five immune signatures were significantly higher in nrTNBCs while lrTNBC were enriched for eight estrogen/luminal signatures (all FDR p<0.05). There was no significant difference in tumor mutation burden or percent genome altered across the groups. Among mutations, only TP53 mutations were significantly more frequent in rrTNBC compared to lrTNBC (Fisher exact FDR p=0.009). To develop an optimal classifier, we used 77 significant clinical and 'omic features to evaluate six modeling approaches encompassing simple, machine learning, and artificial neural network (ANN). Support vector machine outperformed other models with average receiver-operator characteristic area under curve >0.75. Conclusions: We provide a new approach to define TNBCs based on timing of relapse. We identify distinct clinical and genomic features that can be incorporated into machine learning models to predict rapid relapse of TNBC.
191 downloads cancer biology
Small cell lung cancer (SCLC) is the most aggressive subtype of lung cancer with a dismal prognosis. The standard-of-care remains to be uniform treatment with chemotherapy and radiotherapy, even though emerging evidence suggests disease heterogeneity. In primary SCLC, the gene loci for Myc family members are amplified mutually exclusively, their expression is correlated with unique neuroendocrine markers and distinct histopathology of xenografts from SCLC cell lines and murine SCLC. In this study, we explore a novel role of c-Myc and L-Myc as lineage specific factors to bridge the gap between SCLC molecular subtypes and histological classification. Integrated analyses of a Bayesian network generated from primary tumor mRNA expression and chromatin state profiling of cell lines showed that Myc family members impart distinct transcriptional programs associated with lineage state; wherein L-Myc was enriched for neuronal pathways and c-Myc for Notch signaling and epithelial-to-mesenchymal transition. Genetically engineering the exchange of c-Myc with L-Myc in c-Myc amplified SCLC revealed the insufficiency of L-Myc to induce lineage switch but the requirement for c-Myc to maintain NeuroD1-lineage state. In contrast, exogenous expression of c-Myc in L-Myc amplified ASCL1-SCLC revealed incompatibility with c-Myc expression in those SCLC, that eventually trans-differentiated to NeuroD1-SCLC accompanied by variant histopathological features. Transcriptomic profiling of trans-differentiated cells revealed Notch signaling target, Re-1 silencing transcription factor (REST) was induced with c-Myc expression mediating the alteration of ASCL1 expression. Collectively, our findings reveal a previously undescribed role for historically defined general oncogenes, c-Myc and L-Myc, in regulating lineage plasticity across molecular subtypes as well as histological classes.
189 downloads cancer biology
Joanna R Thomas, Kate M Moore, Caroline Sproat, Horacio J. Maldonado-Lorca, Stephanie Mo, Syed Haider, Dean Hammond, Gareth J Thomas, Ian A. Prior, Pedro R Cutillas, Louise J Jones, John F Marshall, Mark R Morgan
The mechanical properties of the extracellular matrix within tumours control multiple cellular functions that drive cancer invasion and metastasis. However, the mechanisms controlling microenvironmental force sensation and transmission, and how these regulate transcriptional reprogramming and invasion, are unclear. Our aim was to understand how mechanical inputs are transmitted bidirectionally and translated into biochemical and transcriptional outputs to drive breast cancer progression. We reveal that adhesion receptor and growth factor receptor crosstalk regulates a bidirectional feedback mechanism co-ordinating force-dependent transcriptional regulation and invasion. Integrin αVβ6 drives invasion in a range of carcinomas and is a potential therapeutic target. αVβ6 exhibits unique biophysical properties that promote force-generation and increase matrix rigidity. We employed an inter-disciplinary approach incorporating proteomics, biophysical techniques and multi-modal live-cell imaging to dissect the role of αVβ6-EGFR crosstalk on transmission of mechanical signals bidirectionally between the extracellular matrix and nucleus. We show that αVβ6 expression correlates with poor prognosis in triple-negative breast cancer (TNBC) and drives invasion of TNBC cells. Moreover, our data show that a complex regulatory mechanism exists involving crosstalk between αVβ6 integrin and EGFR that impacts matrix stiffness, force transmission to the nucleus, transcriptional reprogramming and microenvironment rigidity. αVβ6 engagement triggers EGFR & MAPK signalling and αVβ6-EGFR crosstalk regulates mutual receptor trafficking mechanisms. Consequently, EGF stimulation suppresses αVβ6-mediated force-application on the matrix and nuclear shuttling of force-dependent transcriptional co-activators YAP/TAZ. Finally, we show that crosstalk between αVβ6 & EGFR regulates TNBC invasion. We propose a model whereby αVβ6-EGFR crosstalk regulates matrix stiffening, but also the transmission of extracellular forces into the cell in order to co-ordinate transcriptional reprogramming and invasion. To exploit adhesion receptors and receptor tyrosine kinases therapeutically, it will be essential to understand the integration of their signalling functions and how crosstalk mechanisms influence invasion and the response of tumours to molecular therapeutics.
189 downloads cancer biology
Multiple KRAS G12C inhibitors are in development, and the identification of effective combination treatment regimens should maximize the benefit these agents have on cancer patients. Here, we find that KRAS G12C heterozygous mutated colorectal cancer cells are sensitive to targeting with EGFR therapeutic antibodies. We find that KRAS G12C is partially impaired in binding to tumor suppressor NF1 and also to RAF, and our computational simulations reveal how these deficiencies result in partial sensitivity to EGFR inhibition. For the combination of EGFR and G12C inhibitors we observe synergy and reductions in active forms of both wild-type and mutant RAS. Our simulations reveal the synergy involves both wild-type and mutant RAS. Overall, our work suggests that the addition of an EGFR inhibitor to a KRAS G12C inhibitor regimen should be further evaluated as a strategy for KRAS G12C colorectal cancer patients.
185 downloads cancer biology
Cancer incidence increases exponentially with age, when human telomeres are shorter. Similarly, telomerase mutant zebrafish (tert) have premature short telomeres and anticipate cancer incidence to younger ages. However, because short telomeres constitute a road block to cell proliferation, telomere shortening is currently viewed as a tumor suppressor mechanism and should protect from cancer. This conundrum is not fully understood. In our current study, we report that telomere shortening promotes cancer in a non-cell autonomous manner. Using zebrafish chimeras, we show increased incidence of invasive melanoma when WT tumors are generated in tert mutant zebrafish. tert zebrafish show increased levels of senescence (cdkn2a and ink4a/b) and inflammation (TNF-α). In addition, we transferred second generation tert blastula cells into WT to produce embryo chimeras. Cells with very short telomeres induced senescence and increased neutrophil numbers in surrounding larval tissues in a non-cell autonomous manner, creating an inflammatory environment. Considering that inflammation is pro-tumorigenic, we transplanted melanoma-derived cells into second generation tert zebrafish embryos and observed that tissue environment with short telomeres leads to increased micrometastasis. To test if inflammation was necessary for this effect, we treated melanoma transplants with non-steroid anti-inflammatory drugs and show that higher melanoma invasiveness can be averted. Thus, apart from the cell autonomous role of short telomeres in contributing to genome instability, we propose that telomere shortening with age causes systemic chronic inflammation leading to increased tumor incidence.
184 downloads cancer biology
We have developed a chimeric antigen receptor (CAR) platform that functions as a modular system to address limitations of current CAR therapies. An inert form of the NKG2D extracellular domain (iNKG2D) was used as the ectodomain of the CAR to generate convertibleCAR-T cells. These cells were activated only when an immunological synapse was formed with an antigenic target, mediated by a bispecific adaptor comprised of an iNKG2D-exclusive ULBP2-based ligand fused to an antigen-targeting antibody (MicAbody). Efficacy against Raji tumors in NSG mice was dependent upon doses of both a rituximab-based MicAbody and convertibleCAR-T cells. We have also demonstrated that the exclusive ligand-receptor partnering enabled the targeted delivery of a mutant form of IL-2 to exclusively promote the expansion of convertibleCAR-T cells in vitro and in vivo. By altering the Fv domains of the MicAbody or the payload fused to the orthogonal ligand, convertibleCAR-T cells can be readily targeted or regulated.
181 downloads cancer biology
Aurelie Kamoun, Aurélien de Reyniès, Yves Allory, Gottfrid Sjödahl, A. Gordon Robertson, Roland Seiler, Katherine A Hoadley, Hikmat Al-Ahmadie, Woonyoung Choi, Clarice S. Groeneveld, Mauro A. A. Castro, Jacqueline Fontugne, Pontus Eriksson, Qianxing Mo, Jordan Kardos, Alexandre Zlotta, Arndt Hartmann, Colin P. Dinney, Joaquim Bellmunt, Thomas Powles, Núria Malats, Keith S. Chan, William Y. Kim, David J McConkey, Peter C. Black, Lars Dyrskjot, Mattias Höglund, Seth P. Lerner, Francisco X Real, François Radvanyi, The Bladder Cancer Molecular Taxonomy Group
Muscle-Invasive Bladder Cancer (MIBC) is a molecularly diverse disease with heterogeneous clinical outcomes. Several molecular classifications have been proposed, yielding diverse sets of subtypes. This diversity hampers the clinical application of such knowledge. Here, we report the results of a large international effort to reach a consensus on MIBC molecular subtypes. Using 1750 MIBC transcriptomes and a network-based analysis of six independent MIBC classification systems, we identified a consensus set of six molecular classes: Luminal Papillary (24%), Luminal Non-Specified (8%), Luminal Unstable (15%), Stroma-rich (15%), Basal/Squamous (35%), and Neuroendocrine-like (3%). These consensus classes differ regarding underlying oncogenic mechanisms, infiltration by immune and stromal cells, and histological and clinical characteristics. This consensus system offers a robust framework that will enable testing and validating predictive biomarkers in future clinical trials.
179 downloads cancer biology
A promising, yet still under development approach to cancer treatment is based on the idea of differentiation therapy (DTH). Most tumours are characterised by poorly differentiated cell populations exhibiting a marked loss of traits associated to communication and tissue homeostasis. DTH has been suggested as an alternative (or complement) to cytotoxic-based approaches, and has proven successful in some specific types of cancer such as acute promyelocytic leukemia (APL). While novel drugs favouring the activation of differentiation therapies are being tested, several open problems emerge in relation to its efectiveness on solid tumors. Here we present a mathematical approach to DTH based on a well-known ecological model used to describe habitat loss in a logistic-growing population experiencing death. This model seems to account for some of the observed clinical and in vitro outcomes of DTH while it provides relevant insight into potential treatment scenarios. Furthermore, the same ecological approach is tested in a hierarchical model that accounts for cancer stem cells, proving that DTH might be an effective opportunity to tackle all the self-renewing cellular compartments in a tumor. We show that the lessons learnt from metapopulation ecology can help guide future developments and potential difficulties of DTH.
179 downloads cancer biology
Multiple myeloma (MM) cell lines are routinely used to model the disease. However, a long-standing question is how well these cell lines truly represent tumor cells in patients. Here, we employ a recently-described method of transcriptional correlation profiling to compare similarity of 66 MM cell lines to 779 newly-diagnosed MM patient tumors. We found that individual MM lines differ significantly with respect to patient tumor representation, with median R ranging from 0.35-0.54. ANBL-6 was the top-ranking line, markedly exceeding all others (p < 2.2e-16). Notably, some widely-used cell lines (RPMI-8226, U-266) scored poorly in our patient similarity ranking (48 and 52 of 66, respectively). Lines cultured with interleukin-6 showed significantly improved correlations with patient tumor (p = 9.5e-4). When common MM genomic features were matched between cell lines and patients, only t(4;14) and t(14;16) led to increased transcriptional correlation. To demonstrate utility of our top-ranked line for preclinical studies, we showed that intravenously-implanted ANBL-6 proliferates in hematopoietic organs in immunocompromised mice. Overall, our large-scale quantitative correlation analysis, utilizing emerging datasets, provides a resource informing the MM community of cell lines that may be most reliable for modeling patient disease while also elucidating biological differences between cell lines and tumors.
178 downloads cancer biology
The PI3K/AKT signaling cascade is one of the most commonly dysregulated pathways in cancer, with over half of tumors exhibiting aberrant AKT activation. Although potent small molecule AKT inhibitors have entered clinical trials, robust and durable therapeutic responses have not been observed. As an alternative strategy to target AKT, we report the development of INY-03-041, a pan-AKT degrader consisting of the ATP-competitive AKT inhibitor GDC-0068 conjugated to lenalidomide, a recruiter of the E3 ubiquitin ligase substrate adaptor Cereblon (CRBN). INY-03-041 induced potent degradation of all three AKT isoforms and displayed enhanced anti-proliferative effects relative to GDC-0068. Notably, INY-03-041 promoted sustained AKT degradation and inhibition of downstream signaling effects for up to 96 hours, even after compound washout. Our findings indicate that AKT degradation may confer prolonged pharmacological effects compared to inhibition, and highlight the potential advantages of AKT-targeted degradation.
174 downloads cancer biology
Kevin Kleffman, Grace Levinson, Eitan Wong, Francisco Galán-Echevarría, Richard Von-Itter, Indigo Rose, Lili Blumenberg, Alfredo Floristán, James Tranos, Diana Argibay, Jenny Chen, Avantika Dhabaria, Eleazar de Miera Sainz de Vega, Robert Rogers, Youssef Zaim-Wadghiri, Paul Mathews, Iman Osman, Kelly Ruggles, Beatrix Ueberheide, Shane A. Liddelow, Ronald DeMattos, Yue Ming Li, Robert J. Schneider, Eva Hernando
Brain metastasis is a significant cause of morbidity and mortality in multiple cancer types and represents an unmet clinical need. The mechanisms that mediate metastatic cancer growth in the brain parenchyma are largely unknown. Melanoma, which has the highest rate of brain metastasis among common cancer types, is an ideal model to study how cancer cells adapt to the brain parenchyma. We performed unbiased proteomics analysis of melanoma short-term cultures, a novel model for the study of brain metastasis. Intriguingly, we found that proteins implicated in neurodegenerative pathologies are differentially expressed in melanoma cells explanted from brain metastases compared to those derived from extracranial metastases. This raised the exciting hypothesis that molecular pathways implicated in neurodegenerative disorders are critical for metastatic adaptation to the brain. Here, we show that melanoma cells require amyloid beta (Aβ), a polypeptide heavily implicated in Alzheimer's disease, for growth and survival in the brain parenchyma. Melanoma cells produce and secrete Aβ, which activates surrounding astrocytes to a pro-metastatic, anti-inflammatory phenotype. Furthermore, we show that pharmacological inhibition of Aβ decreases brain metastatic burden. Our results reveal a mechanistic connection between brain metastasis and Alzheimer's disease - two previously unrelated pathologies, establish Aβ as a promising therapeutic target for brain metastasis, and demonstrate suppression of neuroinflammation as a critical feature of metastatic adaptation to the brain parenchyma.
174 downloads cancer biology
Adam W Watson, Adam Grant, Sara S Parker, Michael W Harman, Mackenzie R Roman, Brittany L Forte, Cody C Gowan, Raul Castro-Portuguez, Christian Franck, Darren Cusanovich, Megha Padi, Casey Romanoski, Ghassan Mouneimne
The mechanical microenvironment of primary breast tumors plays a substantial role in promoting tumor progression. While the transitory response of cancer cells to pathological stiffness in their native microenvironment has been well described, it is still unclear how mechanical stimuli in the primary tumor influence distant, late-stage metastatic phenotypes across time and space in absentia. Here, we show that primary tumor stiffness promotes stable, non-genetically heritable phenotypes in breast cancer cells. This mechanical memory instructs cancer cells to adopt and maintain increased cytoskeletal dynamics, traction force, and 3D invasion in vitro, in addition to promoting osteolytic bone metastasis in vivo. Furthermore, we established a mechanical conditioning (MeCo) score comprised of mechanically-regulated genes as a global gene expression measurement of tumor stiffness response. Clinically, we show that a high MeCo score is strongly associated with bone metastasis in patients. Using a discovery approach, we mechanistically traced mechanical memory in part to ERK-mediated mechanotransductive activation of RUNX2, an osteogenic gene bookmarker and bone metastasis driver. The combination of these RUNX2 traits permits the stable transactivation of osteolytic target genes that remain upregulated after cancer cells disseminate from their activating microenvironment in order to modify a distant microenvironment. Using genetic, epigenetic, and functional approaches, we were able to simulate, repress, select and extend RUNX2-mediated mechanical memory and alter cancer cell behavior accordingly. In concert with previous studies detailing the influence of biochemical properties of the primary tumor stroma on distinct metastatic phenotypes, our findings detailing the influence of biomechanical properties support a generalized model of cancer progression in which the integrated properties of the primary tumor microenvironment govern the secondary tumor microenvironment, i.e., soil instructs soil.
174 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 JG 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.
169 downloads cancer biology
Myeloproliferative neoplasms (MPNs) cause the over-production of blood cells such as erythrocytes (polycythemia vera) or platelets (essential thrombocytosis). JAK2 V617F is the most prevalent somatic mutation in many MPNs, but previous modeling of this mutation in mice relied on transgenic overexpression and resulted in diverse phenotypes that were in some cases attributed to expression level. CRISPR-Cas9 engineering offers new possibilities to model and potentially cure genetically encoded disorders via precise modification of the endogenous locus in primary cells. Here we develop scarless Cas9-based reagents to create and reverse the JAK2 V617F mutation in an immortalized human erythroid progenitor cell line (HUDEP-2), CD34+ adult human hematopoietic stem and progenitor cells (HSPCs), and immunophenotypic long-term hematopoietic stem cells (LT-HSCs). We find no overt in vitro increase in proliferation associated with an endogenous JAK2 V617F allele, but co-culture with wild type cells unmasks a competitive growth advantage provided by the mutation. Acquisition of the V617F allele also promotes terminal differentiation of erythroid progenitors, even in the absence of hematopoietic cytokine signaling. Taken together, these data are consistent with the gradually progressive manifestation of MPNs and reveals that endogenously acquired JAK2 V617F mutations may yield more subtle phenotypes as compared to transgenic overexpression models.
168 downloads cancer biology
The ribosome is an RNA-protein complex essential for translation in all domains of life. The structural and catalytic core of the ribosome is its ribosomal RNA (rRNA). While mutations in ribosomal protein (RP) gene are known drivers of oncogenesis, oncogenic rRNA variants have remained elusive. We discovered a cancer-specific single nucleotide variation at 18S.1248U in the 18S rRNA of up to 45.9% colorectal carcinoma (CRC) patients and across >22 cancer types. This is the site of a unique hyper-modified base, 1-methyl-3-α-amino-α-carboxyl-propyl pseudouridine (macpΨ), a modification that is >1 billion years conserved at the ribosome's peptidyl decoding-site. A sub-set of CRC tumors we term 'hypo-macpΨ', show sub-stoichiometric macpΨ-modification unlike normal control tissues. Our macpΨ knockout model and hypo-macpΨ patient tumors share a translational signature, characterized by highly abundant ribosomal proteins. Thus, macpΨ-deficient rRNA forms an uncharacterized class of 'onco-ribosome' which may serve as an innovative chemotherapeutic target for treating cancer patients.
167 downloads cancer biology
Yilong Li, Nicola D. Roberts, Joachim Weischenfeldt, Jeremiah A. Wala, Ofer Shapira, Steven E Schumacher, Ekta Khurana, Jan Korbel, Marcin Imielinski, Rameen Beroukhim, Peter J. Campbell, on behalf of the PCAWG-Structural Variation Working Group, and the PCAWG Network
A key mutational process in cancer is structural variation, in which rearrangements delete, amplify or reorder genomic segments ranging in size from kilobases to whole chromosomes. We developed methods to group, classify and describe structural variants, applied to >2,500 cancer genomes. Nine signatures of structural variation emerged. Deletions have trimodal size distribution; assort unevenly across tumour types and patients; enrich in late-replicating regions; and correlate with inversions. Tandem duplications also have trimodal size distribution, but enrich in early-replicating regions, as do unbalanced translocations. Replication-based mechanisms of rearrangement generate varied chromosomal structures with low-level copy number gains and frequent inverted rearrangements. One prominent structure consists of 1-7 templates copied from distinct regions of the genome strung together within one locus. Such cycles of templated insertions correlate with tandem duplications, frequently activating the telomerase gene, TERT, in liver cancer. Cancers access many rearrangement processes, flexibly sculpting the genome to maximise oncogenic potential.
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