Oncoscience最新文献

{"title":"Phenotypic heterogeneity and cooperation in the metastatic cascade.","authors":"Katherine M Young, Cynthia A Reinhart-King","doi":"10.18632/oncoscience.565","DOIUrl":"https://doi.org/10.18632/oncoscience.565","url":null,"abstract":"proliferative phenotype during the different stages of metastasis, or it works more as a collective movement of go-ers and grow-ers, with migratory cells helping highly proliferative cells reach metastatic sites for colonization, or a combination of both, it is important that we continue to investigate phenotypic subpopulations, both separately and together.","PeriodicalId":19508,"journal":{"name":"Oncoscience","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9499732/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40378346","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MicroRNAs as predictive biomarkers of treatment response to tyrosine kinase inhibitors in hepatocellular carcinoma: how much is missing?","authors":"Laura Gramantieri, Francesca Fornari","doi":"10.18632/oncoscience.564","DOIUrl":"https://doi.org/10.18632/oncoscience.564","url":null,"abstract":"","PeriodicalId":19508,"journal":{"name":"Oncoscience","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9477092/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40373787","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Leveraging the scientific findings to develop therapeutic strategies for dormant breast cancer cells.","authors":"Alejandra Ferrer,&nbsp;Yannick Kenfack,&nbsp;Andrew Petryna,&nbsp;Wadih Arap,&nbsp;Renata Pasqualini,&nbsp;Pranela Rameshwar","doi":"10.18632/oncoscience.562","DOIUrl":"https://doi.org/10.18632/oncoscience.562","url":null,"abstract":"<p><p>Breast cancer (BC) metastasis can occur decades before clinical diagnosis. During this time, the cancer cells (BCCs) can remain dormant for decades. This type of dormancy also occurs during remission where the dormant BCCs adapt cycling quiescence within the tissue microenvironment. BC shows preference for the bone marrow (BM), resulting in poor prognosis. The BM provides a challenge due to the complex niche between the peripheral interface and endosteum. The process of dormancy begins upon entry into the marrow with the changes facilitated through crosstalk between the cancer cells and tissue niche. More importantly, dormancy can occur at any time during the disease process, including the time during treatment. This perspective discusses the challenges posed by the marrow microenvironment to develop treatment. The article discusses the complex mechanisms at each compartment within the marrow niche and the added negative issue of toxicity to the endogenous stem cells.</p>","PeriodicalId":19508,"journal":{"name":"Oncoscience","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9469806/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40362200","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"lncRNA HOTAIR functions and therapeutic perspectives.","authors":"Sabrina Garbo,&nbsp;Marco Tripodi,&nbsp;Cecilia Battistelli","doi":"10.18632/oncoscience.563","DOIUrl":"https://doi.org/10.18632/oncoscience.563","url":null,"abstract":"<p><p>Long non-coding RNAs (lncRNAs) exert central pathophysiological roles through the regulation of gene expression both at transcriptional and post-transcriptional levels. The characterization of lncRNAs' interactome is disclosing several new mechanisms that control disease onset and progression thus opening the way to the development of new pioneering therapeutic approaches. Regarding the lncRNA HOTAIR, found upregulated in several cancers and in liver fibrosis, it has been proved as a potential therapeutic target. HOTAIR acts as a ceRNA for several miRNAs and it directly interacts with chromatin remodelling complexes (e.g. PRC2 and LSD1/NuRD complexes). In this regard, we recently reported the transcription factor SNAIL-mediated recruitment of HOTAIR/PRC2 complex on specific chromatin sites causing epithelial genes' repression through epigenetic chromatin modifications. Conversely, HOTAIR is repressed by the liver-enriched transcriptional factor HNF4a that binds to both HOTAIR promoter and distant enhancer and impairs the formation of a chromatin loop between these genomic regions. In a therapeutic perspective, we design and validated the first example of a dominant negative lncRNA molecule (HOTAIR-sbid) that covers the HOTAIR portion involved in the interaction with SNAIL while is devoid of the domain of interaction with EZH2. Functionally, HOTAIR-sbid expression impairs SNAIL/EZH2/endogenous HOTAIR interaction; thus, PRC2 complex is not recruited on SNAIL-target chromatin sites (i.e. epithelial genes' promoters). Accordingly, the cells rescue an epithelial phenotype, reduce EMT and, in turn, migratory, invasive and anchorage independent growth abilities. This approach promises high level of specificity and limited off-target effects. Future investigations should enhance RNAs' stability and should design strategies for the delivery of these molecules to specific target cells.</p>","PeriodicalId":19508,"journal":{"name":"Oncoscience","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9469907/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40362199","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"As expected, based on rapamycin-like p53-mediated gerosuppression, mTOR inhibition acts as a checkpoint in p53-mediated tumor suppression.","authors":"Mikhail V Blagosklonny","doi":"10.18632/oncoscience.561","DOIUrl":"https://doi.org/10.18632/oncoscience.561","url":null,"abstract":"Recent work by Gu and co-workers (Kon et al., published in 2021), entitled “mTOR inhibition acts as an unexpected checkpoint in p53-mediated tumor suppression”, seemingly “unexpectedly” demonstrated in mice that the ability of p53 to suppress mTOR is essential for tumor suppression early in life [1]. This actually was predicted in 2012 in the commentary entitled “Tumor suppression by p53 without apoptosis and senescence: conundrum or rapalog-like gerosuppression?” [2] [Note: rapalogs are rapamycin analogs]. The commentary [2] was written on another fascinating paper by the same senior author Gu and co-workers (Li et al.) “Tumor suppression in the absence of p53-mediated cell-cycle arrest, apoptosis, and senescence” [3]. Mutant p53 (p53-3KR), constructed by Li et al., lacking all three then-known tumor-suppressing activities, still suppressed tumors [3]. To be precise, as noticed in the commentary [2], there were only two, not three, independent tumor-suppressing activities of p53 known at that time: namely, (i) apoptosis and (ii) cell-cycle arrest/ senescence. Wild-type p53 does not directly induce the senescent phenotype; it induces cell-cycle arrest, which then converts to senescence (geroconversion) without any p53 assistance (Figure 1). When the cell cycle gets arrested by any means (by p53, p21 or anything else), the arrested cell is not yet senescent at first. It will take several days (at least) in cell culture to observe senescent phenotype, including large cell morphology, Senescence-Associated Secretory Phenotype (SASP) and beta-Gal-staining (Figure 1). Geroconversion is driven by growth-promoting pathways such as mTOR and MAPK [4]. In fact, rapamycin and anything that inhibits mTOR such as serum-starvation, contact inhibition and anoxia partially suppresses geroconversion and the senescent phenotype (see for ref. [4]). Then how does p53 causes senescence? It causes cell-cycle arrest, which, in growth-factor rich cell culture, may automatically lead to a senescent phenotype (Figure 2A). [In analogy, a key to your home seemingly has two activities unlock the door and open the door. Yet, it only unlocks the door. When the door is unlocked by the key, you (or the wind) may open the door without key. But if an altered ”mutant” key cannot unlock the door, it cannot help to open it either]. Since mutant p53 (p53-3KR) cannot cause cell-cycle arrest, it cannot cause senescence either. On another hand, Commentary","PeriodicalId":19508,"journal":{"name":"Oncoscience","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9426927/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40343377","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SLFN11's surveillance role in protein homeostasis.","authors":"Yasuhisa Murai,&nbsp;Ukhyun Jo,&nbsp;Yasuhiro Arakawa,&nbsp;Naoko Takebe,&nbsp;Yves Pommier","doi":"10.18632/oncoscience.560","DOIUrl":"https://doi.org/10.18632/oncoscience.560","url":null,"abstract":"The endoplasmic reticulum (ER) is the organelle that produces functional proteins in eukaryotes. However, increased protein synthesis often causes protein misfolding, leading to ER stress and reciprocal activation of the unfolded protein response (UPR). The ubiquitinproteasome system (UPS) and ER stress-associated protein degradation (ERAD) pathways remove immature proteins. Recently, we demonstrated that Schlafen11 (SLFN11) acts as a surveillance factor for protein homeostasis by alleviating the proteotoxic stress derived from protein synthesis and maturation [1]. Schlafen (“to sleep” in German) is the name of a family of genes encompassing SLFN5, SLFN11, SLFN12, SLFN12L, SLFN13, and SLFN14 in human cells. Among the SLFN family, SLFN11 has been identified as a critical determinant for the cytotoxicity of anticancer agents targeting DNA replication across multiple cancer types. SLFN11 is recruited to damaged replication forks under replication stress. It irreversibly inhibits replication by promoting the destabilization of Cdc45-Mcm2-7-GINS (CMG) helicase complex, degrading the Chromatin Licensing and DNA Replication Factor 1 (CDT1), remodeling chromatin, and inducing immediate early genes [2, 3]. Its lack of expression in ~50% of cancer cells leads to chemoresistance. SLFN11 also plays a pivotal role inhibiting viral infection and tumorigenesis [4, 5] (Figure 1). By screening the NCATS drug library, containing 1978 compounds, we recently reported that TAK-243 (MLN7243), a first-in-class inhibitor of the ubiquitinactivating enzyme UBA1 (also known as UBE1) preferentially suppresses cell proliferation of SLFN11deficient cancer cells [1]. TAK-243 binds free ubiquitin to form irreversible ubiquitin adducts and induces ER and proteotoxic stress [6], thereby leading to cancer cell death. We also found that cancer cells that do not express SLFN11 exhibit increased global protein ubiquitylation, ER stress and UPR compared to SLFN11-proficient cells. The increased susceptibility of SLFN11-deficient cells to TAK-243 was associated with an enhanced activation of the UPR transducers PERK, phosphorylated eIF2α, phosphorylated IRE1 and ATF6. Research Perspective","PeriodicalId":19508,"journal":{"name":"Oncoscience","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9313520/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40556595","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Circulating tumor DNA as a therapy response marker in metastatic colorectal cancer.","authors":"Xiaoju Max Ma,&nbsp;Stephanie J Yaung","doi":"10.18632/oncoscience.559","DOIUrl":"https://doi.org/10.18632/oncoscience.559","url":null,"abstract":"","PeriodicalId":19508,"journal":{"name":"Oncoscience","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9232209/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40409697","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rapamycin in the context of Pascal's Wager: generative pre-trained transformer perspective.","authors":"Alex Zhavoronkov","doi":"10.18632/oncoscience.571","DOIUrl":"https://doi.org/10.18632/oncoscience.571","url":null,"abstract":"<p><p>Large language models utilizing transformer neural networks and other deep learning architectures demonstrated unprecedented results in many tasks previously accessible only to human intelligence. In this article, we collaborate with ChatGPT, an AI model developed by OpenAI to speculate on the applications of Rapamycin, in the context of Pascal's Wager philosophical argument commonly utilized to justify the belief in god. In response to the query \"Write an exhaustive research perspective on why taking Rapamycin may be more beneficial than not taking Rapamycin from the perspective of Pascal's wager\" ChatGPT provided the pros and cons for the use of Rapamycin considering the preclinical evidence of potential life extension in animals. This article demonstrates the potential of ChatGPT to produce complex philosophical arguments and should not be used for any off-label use of Rapamycin.</p>","PeriodicalId":19508,"journal":{"name":"Oncoscience","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9796173/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10833464","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Association between tumor mutations and meningioma recurrence in Grade I/II disease.","authors":"Jonathan T Dullea,&nbsp;Vikram Vasan,&nbsp;John W Rutland,&nbsp;Corey M Gill,&nbsp;Danielle Chaluts,&nbsp;Daniel Ranti,&nbsp;Ethan Ellis,&nbsp;Varun Subramanium,&nbsp;Annie Arrighi-Allisan,&nbsp;Yayoi Kinoshita,&nbsp;Russell B McBride,&nbsp;Joshua Bederson,&nbsp;Michael Donovan,&nbsp;Robert Sebra,&nbsp;Melissa Umphlett,&nbsp;Raj K Shrivastava","doi":"10.18632/oncoscience.570","DOIUrl":"https://doi.org/10.18632/oncoscience.570","url":null,"abstract":"<p><strong>Background: </strong>Meningiomas are common intracranial tumors with variable prognoses not entirely captured by commonly used classification schemes. We sought to determine the relationship between meningioma mutations and oncologic outcomes using a targeted next-generation sequencing panel.</p><p><strong>Materials and methods: </strong>We identified 184 grade I and II meningiomas with both >90 days of post-surgical follow-up and linked targeted next-generation sequencing. For mutated genes in greater than 5% of the sample, we computed progression-free survival Cox-regression models stratified by gene. We then built a multi-gene model by including all gene predictors with a <i>p</i>-value of less than 0.20. Starting with that model, we performed backward selection to identify the most predictive factors.</p><p><strong>Results: </strong><i>ATM</i> (HR = 4.448; 95% CI: 1.517-13.046), <i>CREBBP</i> (HR = 2.727; 95% CI = 1.163-6.396), and <i>POLE</i> (HR = 0.544; HR = 0.311-0.952) were significantly associated with alterations in disease progression after adjusting for clinical and pathologic factors. In the multi-gene model, only POLE remained a significant predictor of recurrence after adjusting for the same clinical covariates. Backwards selection identified recurrence status, resection extent, and mutations in <i>ATM</i> (HR = 7.333; 95% CI = 2.318-23.195) and <i>POLE</i> (HR = 0.413; 95% CI = 0.229-0.743) as predictive of recurrence.</p><p><strong>Conclusions: </strong>Mutations in ATM and CREBBP were associated with accelerated meningioma recurrence, and mutations in POLE were protective of recurrence. Each mutation has potential implications for treatment. The effect of these mutations on oncologic outcomes and as potential targets for intervention warrants future study.</p>","PeriodicalId":19508,"journal":{"name":"Oncoscience","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9733702/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10353899","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Potential roles of <i>FAT1</i> somatic mutation in progression of head and neck cancer.","authors":"Zhuo G Chen,&nbsp;Yong Teng","doi":"10.18632/oncoscience.558","DOIUrl":"https://doi.org/10.18632/oncoscience.558","url":null,"abstract":"Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide [1]. It disturbs patients’ vital upper aero-digestive function. Treatment outcomes for patients with HNSCC remain poor in past decades due to the lack of effective therapeutic options, thereby, discovery and evaluation of new medications are of tremendous importance for improving patients’ survival. Human papillomavirus (HPV) status remains one of strong indicators of survival, however, HPV-unrelated disease carrying a 5-year overall survival (OS) rate of less than 50% [2]. The challenges in effectively treating HNSCC are attributed to its extreme heterogeneity as far as anatomic locations and genetic aberrations. Major gaps in understanding the biology of disease continue to be the main reason behind the paucity of effective therapeutic interventions. FAT1 encodes a member of the cadherin-like protein family. Under normal physiological conditions, FAT1 serves as a molecular “brake” on mitochondrial respiration [3] and acts as a receptor for a signaling pathway regulating cell-cell contact interaction and planar cell polarity [4, 5]. Loss of fat leads to cell cycle dysregulation and hyperproliferation in Drosophila larval imaginal discs [6]. Recently, FAT1 mutations were identified in human cancers and may contribute to Wnt activation, suggesting that FAT1 may serve as a tumor suppressor in human cells [7]. The FAT1 mutant was found to inactivate the Hippo regulatory complex, which leads to activation of YAP1 in HNSCC as reported by Martin et al. They also indicated that the FAT1 gene alteration rate was as high as 29.8% in HNSCC, which is the highest among solid tumors [8]. FAT1 mutation was reported to be more common in HPV-negative (HPV−) than in HPV-positive (HPV+) HNSCC (28% vs. 2.8%). Mann et al., examined 16 HNSCC cell lines and reported a FAT1 mutation rate of 43% [9]. One recent study on Research Perspective","PeriodicalId":19508,"journal":{"name":"Oncoscience","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9098264/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10598660","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}