bioRxiv - Cancer Biology最新文献

{"title":"Allele-specific expression is selected in tumorigenesis, results from epigenetic changes and has prognostic relevance","authors":"Guillermo Palou-Márquez, Pere Pericot-Masdevall, Fran Supek","doi":"10.1101/2024.09.07.611780","DOIUrl":"https://doi.org/10.1101/2024.09.07.611780","url":null,"abstract":"Allele-specific expression (ASE) is the differential abundance in levels of mRNAs that originated from the paternal and maternal copies of a gene. Such allelic imbalances can contribute to phenotypic variation and influence disease traits, including cancer. There is common ASE in tumors that results from somatic copy-number alterations (CNAs) at the DNA level, but there also exist other causes of ASE: cis-acting genetic or epigenetic variation that can lead to differential expression between the two alleles. However, the latter, non-CNA mechanisms of ASE remain understudied in cancer, as well as their role in tumor evolution and impact on clinical outcomes. By integrating a wide variety of genomic and transcriptomic pan-cancer data from the TCGA project, we show that ASE favoring the preferential expression of the mutant allele in some driver genes is subject to positive selection, and that these events are associated with worse overall survival across all cancer types. We found that the impact of ASE triggered by non-CNA causes is substantial, and we propose that some instances of cis-ASE are explained by the epigenetic changes affecting alleles differently. Furthermore, as a second mechanism, we find that splicing-altering mutations are selected in various cancer genes and result in ASE. We anticipate that the study and understanding of the role of mutant allele imbalances at the mRNA level can help understand epigenetic changes during cancer evolution, as well as identify new prognostic markers and therapeutic approaches that target altered allelic expression in tumors.","PeriodicalId":501233,"journal":{"name":"bioRxiv - Cancer Biology","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142210473","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Urinary multi-omics reveal non-invasive diagnostic biomarkers in clear cell renal cell carcinoma","authors":"Gustav Jonsson, Maura Hofmann, Tiago Oliveira, Ursula Lemberger, Karel Stejskal, Gabriela Krssakova, Irma Sakic, Maria Novatchkova, Stefan Mereiter, Gerlinde Grabmann, Thomas Koecher, Zeljko Kikic, Gerald N. Rechberger, Thomas Zuellig, Bernhard Englinger, Manuela Schmidinger, Josef M. Penninger","doi":"10.1101/2024.08.12.607453","DOIUrl":"https://doi.org/10.1101/2024.08.12.607453","url":null,"abstract":"Clear cell renal cell carcinoma (ccRCC) is the kidney malignancy with the highest incidence and mortality rates. Despite the high patient burden, there are no biomarkers for rapid diagnosis and public health surveillance. Urine would be an ideal source of ccRCC biomarkers due to the low invasiveness, easy accessibility, and the kidney's intrinsic role in filtering urine. In the present work, by combining proteomics, lipidomics and metabolomics, we detected urogenital metabolic dysregulation in ccRCC patients with increased lipid metabolism, altered mitochondrial respiration signatures and increased urinary lipid content. Importantly, we identify three early-stage diagnostic biomarkers for ccRCC in urine samples: Serum amyloid A1 (SAA1), Haptoglobin (HP) and Lipocalin 15 (LCN15). We further implemented a parallel reaction monitoring mass spectrometry protocol for rapid and sensitive detection of SAA1, HP and LCN15 and combined all three proteins into a diagnostic UrineScore. In our discovery cohort, this score had a performance accuracy of 96% in receiver operating characteristic curve (ROC) analysis for classification of ccRCC versus control cases. Our data identifies tractable and highly efficacious urinary biomarkers for ccRCC diagnosis and serve as a first step towards the development of more rapid and accessible urinary diagnostic platforms.","PeriodicalId":501233,"journal":{"name":"bioRxiv - Cancer Biology","volume":"33 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142210472","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Graph Curvature-Based Pipeline for Discovering Immune Checkpoint Response Biomarkers","authors":"James J Bannon, Charles R. Cantor, Bud Mishra","doi":"10.1101/2024.09.04.611306","DOIUrl":"https://doi.org/10.1101/2024.09.04.611306","url":null,"abstract":"Immune checkpoint inhibitors (ICIs), also called immune checkpoint blockers, are a promising category of targeted therapy for solid tumors. Predicting which patients will respond to ICI therapy remains an open problem under active investigation. This paper adds to this effort by developing a modular pipeline for the discovery of biomarkers from tumor RNA-sequencing data. We contextualize gene expression measurements using a protein-protein interaction (PPI) network and use a notion of graph curvature to find (pairs of) genes in the PPI that could serve as potential biomarkers. Our candidate biomarkers are evaluated using an extensive literature search and transfer learning experiments. We also provide a harmonized collection of drug-specific candidate markers found through rank aggregation that we believe merit further study.","PeriodicalId":501233,"journal":{"name":"bioRxiv - Cancer Biology","volume":"85 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142210475","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discordance in acute gastrointestinal toxicity between synchrotron-based proton and linac-based electron ultra-high dose rate irradiation","authors":"Kevin Liu, Uwe Titt, Nolan M Esplen, Luke Connell, Elise K Konradsson, Ming Yang, Xiaochun Wang, Takeshi Takaoka, Ziyi Li, Albert C Koong, Devarati Mitra, Radhe Mohan, Billy W Loo, Steven H Lin, Emil Schueler","doi":"10.1101/2024.09.04.611307","DOIUrl":"https://doi.org/10.1101/2024.09.04.611307","url":null,"abstract":"Purpose: Proton FLASH has been investigated using cyclotron and synchrocyclotron beamlines but not synchrotron beamlines. We evaluated the impact of dose rate (ultra-high [UHDR] vs. conventional [CONV]) and beam configuration (shoot-through [ST] vs. spread-out-Bragg-peak [SOBP]) on acute radiation-induced gastrointestinal toxicity (RIGIT) in mice. We also compared RIGIT between synchrotron-based protons and linac-based electrons with matched mean dose rates.\u0000Methods and Materials: We administered abdominal irradiation (12-14 Gy single fraction) to female C57BL/6J mice with an 87 MeV synchrotron-based proton beamline (2 cm diameter field size as a lateral beam). Dose rates were 0.2 Gy/s (S-T pCONV), 0.3 Gy/s (SOBP pCONV), 150 Gy/s (S-T pFLASH), and 230 Gy/s (SOBP pFLASH). RIGIT was assessed by the jejunal regenerating crypt assay and survival. We also compared responses to proton [pFLASH and pCONV] with responses to electron CONV (eCONV, 0.4 Gy/s) and electron FLASH (eFLASH, 188-205 Gy/s).\u0000Results: The number of regenerating jejunal crypts at each matched dose was lowest for pFLASH (similar between S-T and SOBP), greater and similar between pCONV (S-T and SOBP) and eCONV, and greatest for eFLASH. Correspondingly, mice that received pFLASH SOBP had the lowest survival rates (50% at 50 days), followed by pFLASH S-T (80%), and pCONV SOBP (90%), but 100% of mice receiving pCONV S-T survived (log-rank P = 0.047 for the four groups).\u0000Conclusions: Our findings are consistent with an increase in RIGIT after synchrotron-based pFLASH versus pCONV. This negative proton-specific FLASH effect versus linac-based electron irradiation underscores the importance of understanding the physical and biological factors that will allow safe and effective clinical translation.","PeriodicalId":501233,"journal":{"name":"bioRxiv - Cancer Biology","volume":"58 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142210477","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MYC plus class IIa HDAC inhibition potentiates mitochondrial dysfunction in non-small cell lung cancer","authors":"Jina Park, Ying-Yu Chen, Jennie J. Cao, Julia An, Ray-Whay Chiu Yen, John D. Outen, Stephen B. Baylin, Michael J. Topper","doi":"10.1101/2024.09.04.610116","DOIUrl":"https://doi.org/10.1101/2024.09.04.610116","url":null,"abstract":"MYC is frequently activated in cancer, leading to significant efforts to develop MYC inhibitors. While much progress has been made in targeting MYC, combination treatment strategies are needed to exploit this molecular vulnerability. To this end, we interrogated transcriptome data from cancer cell lines treated with MYC inhibitors and identified HDAC5 and HDAC9, both class IIa HDACs, as therapeutic targets to inhibit concurrently. Notably, these HDAC isoforms, which can be specifically targeted by small molecules, are known augmenters of several hallmarks of cancer. The combination of MYC and class IIa HDAC inhibition induces a significant reduction in viability for NSCLC cell lines with high MYC and mitochondrial pathway activation. Additionally, combination treatment induces a robust reduction of MYC with concomitant elevation of mitochondrial ROS, both of which have a causal relationship with therapeutic efficacy. Confirmation of in vivo efficacy was pursued in several animal model systems, with subsequent molecular correlate derivation confirming the importance of MYC depletion and mitochondrial dysfunction in driving drug efficacy. Ultimately, we define a therapeutic approach combining MYCi and class IIa HDACi to potentiate anti-tumor efficacy in NSCLC.","PeriodicalId":501233,"journal":{"name":"bioRxiv - Cancer Biology","volume":"4 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142210474","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Caveolin-1 and mechanical stress control the release of a pro-metastatic subpopulation of small extracellular vesicles","authors":"Cristian Saquel, Celine Gracia, Christine Viaris de Lesegno, Frederik Verweij, Carlos Urena-Martin, Graca Raposo, Christophe Lamaze","doi":"10.1101/2024.09.05.611225","DOIUrl":"https://doi.org/10.1101/2024.09.05.611225","url":null,"abstract":"Extracellular vesicles are lipid-enclosed vesicles released by most cells and are present in all human bodily fluids. EVs carry genetic material and proteins, which can be transferred to other cells, generating various biological effects. Caveolin-1 (Cav1) is a key structural protein of the small invaginations of the plasma membrane known as caveolae, which function as mechano-sensors and membrane tension buffering devices. Elevated levels of Cav1 have been detected in EVs from patients with advanced cancer. Given the importance of mechanical forces within the tumor microenvironment, we investigated the potential role of caveolae and/or Cav1 in regulating EV dynamics and cancer progression under mechanical stress. Our study revealed that different types of mechanical stress induced significantly increased the release of EVs from several cancer cell lines. These EVs were characterized as exosomes enriched with Cav1. Notably, we found that functional Cav1 was essential for the stress-induced increase in EV production. Lipidomic and proteomic analyses showed differences in the composition of EVs between WT and Cav1-deficient cells and between resting cells and cells subjected to mechanical stress. Additionally, EVs isolated from mechanically stressed cells were shown to promote enhanced migration and invasion of cancer cells in a Cav1-dependent manner. Altogether, our data uncover a new role for Cav1 in mediating cell-to-cell communication and promoting the acquisition of metastatic traits through the mechanical regulation of EV production and dynamics.","PeriodicalId":501233,"journal":{"name":"bioRxiv - Cancer Biology","volume":"20 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142210492","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Combination of cycling hyperthermia and Echinacoside creates synergistic curing effect on pancreatic cancer PANC-1 cells","authors":"Wei-Ting Chen, You-Ming Chen, Guan-Bo Lin, Yu-Yi Kuo, Hsu-Hsiang Liu, Chih-Yu Chao","doi":"10.1101/2024.09.04.611320","DOIUrl":"https://doi.org/10.1101/2024.09.04.611320","url":null,"abstract":"Therapy targeting the suppression of human MutT homolog 1 (MTH1) has been gaining ground in recent years, thanks to its resulting significant increase of 8-hydroxy-2'-deoxyguanosine triphosphate (8-oxo-dGTP) accumulation in genomic DNA, causing DNA damage and apoptotic cell death. Echinacoside (Ech), a natural phenylethanoid glycoside first extracted from Echinacea angustifolia or desert plant Cistanches is one of a few natural products which are capable of inhibiting the MTH1 function. It, however, is difficult to apply it in clinical trials, due to high cost for effective dosage in need. In the study, we show that combination with thermal-cycling hyperthermia (TC-HT), a novel physical treatment, can amplify the curative effect of Ech, reducing its dosage in need significantly. The combination resulted in a multipronged mechanism targeting multiple key apoptotic regulating proteins such as Bcl-2 and MAPK family proteins. Its effect is expected to be comparable to the treatment strategy containing MTH1, Bcl-2, and ERK inhibitors, posing as new promising approach in cancer treatment.","PeriodicalId":501233,"journal":{"name":"bioRxiv - Cancer Biology","volume":"6 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142210476","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Claudin-4 remodeling of nucleus-cell cycle crosstalk maintains ovarian tumor genome stability and drives resistance to genomic instability-inducing agents.","authors":"Benjamin G Bitler, Fabian R. Villagomez, Julie Lang, Daniel Nunez-Avellaneda, Kian Behbakht, Hannah L. Dimmick, Patricia Webb, Kenneth P. Nephew, Margaret Neville, Elizabeth R. Woodruff","doi":"10.1101/2024.09.04.611120","DOIUrl":"https://doi.org/10.1101/2024.09.04.611120","url":null,"abstract":"During cancer development, the interplay between the nucleus and the cell cycle leads to a state of genomic instability, often accompanied by observable morphological aberrations. These aberrations can be controlled by tumor cells to evade cell death, either by preventing or eliminating genomic instability. In epithelial ovarian cancer (EOC), overexpression of the multifunctional protein claudin-4 is a key contributor to therapy resistance through mechanisms associated with genomic instability. However, the molecular mechanisms underlying claudin-4 overexpression in EOC remain poorly understood. Here, we altered claudin-4 expression and employed a unique claudin-4 targeting peptide (CMP) to manipulate the function of claudin-4. We found that claudin-4 facilitates genome maintenance by linking the nuclear envelope and cytoskeleton dynamics with cell cycle progression. Claudin-4 caused nuclei constriction by excluding lamin B1 and promoting perinuclear F-actin accumulation, associated with remodeling nuclear architecture, thus altering nuclear envelope dynamics. Consequently, cell cycle modifications due to claudin-4 overexpression resulted in fewer cells entering the S-phase and reduced genomic instability. Importantly, disrupting biological interactions of claudin-4 using CMP and forskolin altered oxidative stress cellular response and increased the efficacy of PARP inhibitor treatment. Our data indicate that claudin-4 protects tumor genome integrity by remodeling the crosstalk between the nuclei and the cell cycle, leading to resistance to genomic instability formation and the effects of genomic instability-inducing agents.","PeriodicalId":501233,"journal":{"name":"bioRxiv - Cancer Biology","volume":"85 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142210497","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"On the equivalence between Agent-Based and Continuum models for cell population modeling. Application to glioblastoma evolution in microfluidic devices","authors":"Raquel B. Arroyo-Vazquez, Marina Perez-Aliacar, Jacobo Ayensa-Jimenez, Manuel Doblare","doi":"10.1101/2024.09.05.611243","DOIUrl":"https://doi.org/10.1101/2024.09.05.611243","url":null,"abstract":"Mathematical models are invaluable tools for understanding the mechanisms and interactions that control the behavior of complex systems. Modeling a problem as cancer evolution includes many coupled phenomena being therefore impossible to obtain sufficient experimental results to fully evaluate all possible conditions. In this work, we focus on Agent-Based Models (ABMs), as these models allow to obtain more complete and interpretable information at the individual level than other types of in silico models. However, ABMs, need many parameters, requiring more information at the cellular and environmental levels to be calibrated. To overcome this problem we propose a complementary approach to traditional calibration methods. We used existent continuum models able to reproduce experimental data, validated and with fitted parameters, to establish relationships between parameters of both, continuum and agent-based models, to simplify and improve the process of adjusting the parameters of the ABM. With this approach, it is possible to bridge the gap between both kinds of models, allowing to work with them simultaneously and take advantage of the benefits of each of them. To illustrate this methodology, the evolution of glioblastoma (GB) is modeled as an example of application. The resulting ABM obtains very similar results to those previously obtained with the continuum model, replicating the main histopathological features (the formation of necrotic cores and pseudopalisades) appearing in several different in vitro experiments in microfluidic devices, as we previously obtained with continuum models. However, ABMs have additional advantages: since they also incorporates the inherent random effects present in Biology, providing a more natural explanation and a deeper understanding of biological processes. Moreover, additional relevant phenomena can be easily incorporated, such as the mechanical interaction between cells or with the environment, angiogenic processes and cell concentrations far from the continuum requirement as happens, for intance, with immune cells.","PeriodicalId":501233,"journal":{"name":"bioRxiv - Cancer Biology","volume":"9 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142210494","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Interplay of ferroptotic and apoptotic cell death and its modulation by BH3-mimetics","authors":"Yun Qiu, Juliana A. Hüther, Bianca Wank, Antonia Rath, René Tykwe, Sabine Laschat, Marcus Conrad, Daniela Stöhr, Markus Rehm","doi":"10.1101/2024.09.04.611207","DOIUrl":"https://doi.org/10.1101/2024.09.04.611207","url":null,"abstract":"Ferroptosis and apoptosis are widely considered to be independent cell death modalities. Ferroptotic cell death is a consequence of insufficient radical detoxification and progressive lipid peroxidation, which is counteracted by glutathione peroxidase 4 (GPX4). Apoptotic cell death can be triggered by a wide variety of stresses, including oxygen radicals, and can be suppressed by anti-apoptotic members of the BCL-2 protein family. Mitochondria are the main interaction site of BCL-2 family members and likewise a major source of oxygen radical stress. We therefore studied if ferroptosis and apoptosis might intersect and possibly interfere with one another. Indeed, cells dying from impaired GPX4 activity displayed hallmarks of both ferroptotic and apoptotic cell death, with the latter including (transient) membrane blebbing, submaximal cytochrome-c release and caspase activation. Targeting BCL-2, MCL-1 or BCL-XL with BH3-mimetics under conditions of moderate ferroptotic stress in many cases synergistically enhanced overall cell death and frequently skewed primarily ferroptotic into apoptotic outcomes. Surprisingly though, in other cases BH3-mimetics, most notably the BCL-XL inhibitor WEHI-539, counter-intuitively suppressed cell death and promoted cell survival following GPX4 inhibition. Further studies revealed that most BH3-mimetics possess previously undescribed antioxidant activities that counteract ferroptotic cell death at commonly employed concentration ranges. Our results therefore show that ferroptosis and apoptosis can intersect. We also show that combining ferroptotic stress with BH3-mimetics, context-dependently can either enhance and convert cell death outcomes between ferroptosis and apoptosis or can also suppress cell death by intrinsic antioxidant activities.","PeriodicalId":501233,"journal":{"name":"bioRxiv - Cancer Biology","volume":"25 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142210498","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}