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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 62,745 bioRxiv papers from 278,406 authors.

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in category cancer biology

2,031 results found. For more information, click each entry to expand.

1921: Targeting MEK5 impairs non-homologous end-joining repair and sensitizes prostate cancer to DNA damaging agents
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Posted to bioRxiv 15 Aug 2019

Targeting MEK5 impairs non-homologous end-joining repair and sensitizes prostate cancer to DNA damaging agents
78 downloads cancer biology

Constantinos G. Broustas, Axel J Duval, Kunal R. Chaudhary, Richard A. Friedman, Renu K. Virk, Howard B. Lieberman

Radiotherapy is commonly used to treat a variety of solid human tumors, including localized prostate cancer. However, treatment failure often ensues due to tumor intrinsic or acquired radioresistance. Here we find that the MEK5/ERK5 signaling pathway is associated with resistance to genotoxic stress in aggressive prostate cancer cells. MEK5 knockdown by RNA interference sensitizes prostate cancer cells to ionizing radiation (IR) and etoposide treatment, as assessed by clonogenic survival and short-term proliferation assays. Mechanistically, MEK5 downregulation impairs phosphorylation of the catalytic subunit of DNA-PK at serine 2056 in response to IR or etoposide treatment. Although MEK5 knockdown does not influence the initial appearance of radiation- and etoposide-induced γH2AX and 53BP1 foci, it markedly delays their resolution, indicating a DNA repair defect. A cell-based assay shows that non-homologous end joining (NHEJ) is compromised in cells with ablated MEK5 protein expression. Finally, MEK5 silencing combined with focal irradiation causes strong inhibition of tumor growth in mouse xenografts, compared with MEK5 depletion or radiation alone. These findings reveal a convergence between MEK5 signaling and DNA repair by NHEJ in conferring resistance to genotoxic stress in advanced prostate cancer and suggest targeting MEK5 as an effective therapeutic intervention in the management of this disease.

1922: Di-Ras2 Promotes Renal Cell Carcinoma Formation by Activating the MAPK Pathway in the Absence of VHL
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Posted to bioRxiv 27 Jun 2019

Di-Ras2 Promotes Renal Cell Carcinoma Formation by Activating the MAPK Pathway in the Absence of VHL
78 downloads cancer biology

Hanyu Rao, Xuefeng Li, Min Liu, Jing Liu, Xiaoxue Li, Jin Xu, Li Li, Wei-Qiang Gao

Clear cell renal cell carcinoma (ccRCC) is one of the most common and lethal human urological malignancies in the world. The pathological drivers for ccRCC are still poorly understood. One of them is the Ras family of small GTPases that function as "molecular switches" in many diseases including ccRCC. Among them, Di-Ras2 encodes a 26-kDa GTPase that shares 60% homology to Ras and Rap. Yet little is known about the biological function(s) of Di-Ras2. In this study, we found that Di-Ras2 was upregulated in ccRCC, and promoted the proliferation, migration and invasion of human ccRCC cells in the absence of von Hippel-Lindau (VHL). Mechanistically, Di-Ras2 induces and regulates ccRCC formation by modulating phosphorylation of the downstream effectors and activating the MAPK signaling pathway. Moreover, Di-Ras2 interacts with E3 ubiquitin ligase, VHL, which facilitates the ubiquitination and degradation of Di-Ras2. Together, these results indicate a potential function of Di-Ras2 as an oncogene and biomarker in ccRCC, and these data provide a new perspective of the relationship between VHL and the MAPK pathway in ccRCC tumorigenesis.

1923: Natural IgE promotes epithelial hyperplasia and inflammation-driven tumour growth
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Posted to bioRxiv 30 Sep 2019

Natural IgE promotes epithelial hyperplasia and inflammation-driven tumour growth
78 downloads cancer biology

Mark David Hayes, Sophie Ward, Greg Crawford, Rocio Castro Seoane, William David Jackson, David Kipling, David Voehringer, Deborah Dunn-Walters, Jessica Strid

IgE is the least abundant circulating antibody class but is constitutively present in healthy tissues bound to resident cells via its high-affinity receptor, FcεRI. The physiological role of endogenous IgE is unclear but it is suggested to provide host protection against a variety of noxious environmental substances and parasitic infections at epithelial barrier surfaces. Here we show that skin inflammation enhances levels of IgE with natural specificities and with a similar repertoire, VDJ rearrangements and CDRH3 characteristics as in healthy tissue. IgE-bearing basophils are recruited to inflamed skin via CXCL12 and TSLP/IL-3-dependent upregulation of CXCR4. In the inflamed skin, IgE/FcεRI-signalling in basophils promotes epithelial cell growth and differentiation, partly through histamine engagement of H1R and H4R. Furthermore, this natural IgE response strongly drives tumour outgrowth of epithelial cells harbouring oncogenic mutation. These findings indicate that natural IgE support skin barrier defences however during chronic tissue inflammation this may be subverted to promote tumour growth.

1924: Killer Immunoglobulin-like Receptor-Ligand Interactions Predict Clinical Outcomes Following Unrelated Donor Transplants
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Posted to bioRxiv 23 Jun 2019

Killer Immunoglobulin-like Receptor-Ligand Interactions Predict Clinical Outcomes Following Unrelated Donor Transplants
78 downloads cancer biology

Elizabeth Krieger, Roy Sabo, Sanauz Moezzi, Caitlin Cain, Catherine Roberts, Pamela Kimball, Alden Chesney, John McCarty, Armand Keating, Rizwan Romee, Christina Wiedl, Rehan Qayyum, Amir Toor

Killer immunoglobulin-like receptor (KIR) and KIR-ligand (KIRL) interactions play an important role in natural killer (NK) cell mediated graft versus leukemia effect following hematopoietic cell transplantation (HCT). However, there is considerable heterogeneity in the KIR gene and KIRL content in individuals, making it difficult to estimate the full clinical impact of NK cell reconstitution following HCT. Herein a novel mathematical model designed to quantify these interactions is presented to better assess the influence of NK cell-mediated alloreactivity on transplant outcomes. Ninety-eight HLA matched unrelated donor (URD) HCT recipients were retrospectively studied. The KIR-KIRL interactions were quantified using a system of matrix equations. Unit values were ascribed to each KIR-KIRL interaction and directionality of interactions was denoted by, either a positive (activating) or negative symbol (inhibition); these interactions were then summed. The absolute values of both the missing KIRL as well as inhibitory KIR-KIRL interactions were significantly associated with overall survival and relapse. These score components were initially used to develop a weighted (w-KIR Score) and subsequently a simplified, non-weighted KIR-KIRL interaction scores (IM-KIR Score). Increased w-KIR Score and IM-KIR Score were both predictive of all-cause mortality and relapse; w-KIR score HR of 0.37 (P=0.001) and 0.44 (P=0.044) respectively; IM-KIR score HR of 0.5 (P=0.049) and 0.44 (P=0.002) respectively. IM-KIR score was also associated with NK cell reconstitution post HCT. KIR-KIRL interactions as reflected by the w-KIR and IM-KIR scores influence both relapse risk and survival in recipients of HLA matched URD HCT with hematological malignancies.

1925: Dynamic urinary proteomic analysis in a Walker 256 intracerebral tumor model
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Posted to bioRxiv 02 Dec 2018

Dynamic urinary proteomic analysis in a Walker 256 intracerebral tumor model
77 downloads cancer biology

Linpei Zhang, Yuqiu Li, Wenshu Meng, Yanying Ni, Youhe Gao

Patients with primary and metastatic brain cancer have an extremely poor prognosis, mostly due to the late diagnosis of disease. Urine, which lacks homeostatic mechanisms, is an ideal biomarker source that accumulates early and highly sensitive changes to provides information about the early stage of disease. A rat model mimicking the local tumor growth process in the brain was established with intracerebral Walker 256 (W256) cell injection. Urine samples were collected on days 3, 5 and 8 after injection and then analyzed by LC-MS/MS. In the intracerebral W256 model, no obvious clinical manifestations changes or abnormal MRI signals were found on days 3 and 5; at these time points, nine proteins were changed significantly in the urine of all 8 tumor rats. On day 8, when tumors were detected by MRI, twenty-five differential proteins were identified, including 10 proteins that have been reported to be closely related to tumor metastasis or brain tumors. The differential urinary proteomes were compared with those from the subcutaneous W256 model and the intracerebral C6 model. Few differential proteins overlapped. Specific differential protein patterns were observed among the three models, indicating that the urinary proteome can reflect the difference when tumor cells with different growth characteristics are inoculated into the brain and when identical tumor cells are inoculated into different areas, specifically, the subcutis and the brain.

1926: Medroxyprogesterone reverses tolerable dose metformin-induced inhibition of invasion via matrix metallopeptidase-9 and transforming growth factor-β1 in KLE endometrial cancer cells
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Posted to bioRxiv 02 Apr 2019

Medroxyprogesterone reverses tolerable dose metformin-induced inhibition of invasion via matrix metallopeptidase-9 and transforming growth factor-β1 in KLE endometrial cancer cells
77 downloads cancer biology

Dong Hoon Suh, Sunray Lee, Hyun-Sook Park, Noh Hyun Park

This study was performed to evaluate the anticancer effects of tolerable doses of metformin with or without medroxyprogesterone (MPA) in endometrial cancer cells. Cell viability, cell invasion, and levels of matrix metallopeptidase (MMP) and transforming growth factor (TGF)-β1 were analyzed using three human endometrial adenocarcinoma cell lines (Ishikawa, KLE, and USPC) after treatment with different dose combinations of MPA (0, 10 µM) and metformin (0, 100, 1000 µM). Combining metformin (0, 100, 1000 µM) and 10 µM MPA induced significantly decreased cell viability in a time- and dose-dependent manner in Ishikawa cells, but not in KLE and USPC cells. There was no dose- or time-dependent cell growth inhibition, or positive western blot results for the expression of progesterone receptors and phospho-AMPKα, following treatment with any combination of metformin (0, 100, 1000 µM) and 10 µM MPA in KLE and USPC cells. In KLE cells, metformin treatment alone significantly inhibited cell invasion in a dose-dependent manner (1.31±0.05, 0.94±0.04, 0.83±0.05 at 0, 100 µM, 1000 µM, respectively; p<0.0005). The inhibitory effect of metformin was reversed to create a stimulating effect when metformin was combined with 10 µM MPA (1.10±0.05, 1.42±0.18, 1.41±0.26 at 0, 100, 1000 µM, respectively; p<0.005). MMP-9 and TGF-β1 showed similar trends in terms of cell invasion in KLE cells. In conclusion, the anti-invasive effect of metformin in KLE cells was completely reversed to the state of no treatment by the addition of MPA; this might be mediated through MMP-9 and TGF-β1. Our study suggests the possibility of these combinations doing harm, rather than good, under some conditions.

1927: Galectin-14 expression in ovarian cancer.
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Posted to bioRxiv 28 Jul 2019

Galectin-14 expression in ovarian cancer.
77 downloads cancer biology

Lorenna Oliveira Fernandes de Araujo, Yves St-Pierre

Galectins (gal) are multifunctional proteins whose expression changes under different physiological or pathological conditions, including cancer. However, so far, most studies have focused on gal-1 and gal-3, and to a lesser extent to gal-7 and gal-9. We still know very little about other galectins, especially the recently discovered ones, such as gal-14, a prototype galectin highly expressed at the maternal-fetal interface. Here, using in silico and in vitro approaches, we report a correlation between lgals14 expression and ovarian cancer. We found that high expression of gal-14 mRNA in ovarian cancer cells is associated with a shorter survival. Consistent with this observation, we also found that lgals14 is preferentially expressed in high grade serous adenocarcinoma (HGSA) ovarian cancer. Our in vitro data with ovarian cancer cell lines confirmed that lgals14 is readily expressed in HGSA. Interestingly, de novo expression of gal-14 in HEK-293 cells increased apoptosis, both at the basal level and following exposure to low doses of etoposide. Thus, although the study of this galectin is still in its infancy, we were able to provide novel insights into the expression patterns of this galectin and its involvement in cancer.

1928: Close homologue of L1 sensitizes lung cancer cells to cisplatin and paclitaxel via inhibition Akt pathway
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Posted to bioRxiv 28 Aug 2019

Close homologue of L1 sensitizes lung cancer cells to cisplatin and paclitaxel via inhibition Akt pathway
77 downloads cancer biology

Xiangdao Cai, Bang Hu, Sheng Liu, Maolin Liu, Yunhe Huang, Peng Lei, Zhi Zhang, Zhiwei He, Linquan Zhang, Ruimao Huang

Drug resistance is a serious promble during chemotherapy in lung cancer, which may lead to tumor relapse and further progression. CHL1 was a tumor suppressor in most malignancies, and it was found downregulated in NSCLC cisplatin-resistant cells H460. Thus, in this study, we investigated the role and mechanism of chemoresistance by CHL1 in lung cancer. Human lung adenocarcinoma cell lines A549 and its cisplatin resistant cells (A549/DDP) and paclitaxel resistant cells (A549/PTX) were applied in this research. CHL1 was found obvious downregulation in A549/DDP and A549/PTX cells versus A549 cells. Suppression of CHL1 in A549 cells, promoted cell survival rate and clone formation, decreased cell apoptosis when treated with or without DDP and PTX, respectively. While excessive CHL1 expression in A549/DDP and A549/PTX cells, the results were opposite. Moreover, CHL1 knockdown mediating chemoresistance was reversed by Akt inhibitor SC66 in A549 cells. In summary, overexpression of CHL1 reversed chemoresistance to cisplatin and PTX via suppressing Akt pathway in lung cancer, it was suggested that CHL1 maybe as a potential target for overcome chemoresistance in lung cancer.

1929: Pivotal involvement of the CX3CL1-CX3CR1 axis for the recruitment of M2-TAMs in skin carcinogenesis
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Posted to bioRxiv 14 Jul 2019

Pivotal involvement of the CX3CL1-CX3CR1 axis for the recruitment of M2-TAMs in skin carcinogenesis
76 downloads cancer biology

Yuko Ishida, Yumi Kuninaka, Yuki Yamamoto, Mizuho Nosaka, Akihiko Kimura, Fukumi Furukawa, Naofumi Mukaida, Toshikazu Kondo

We previously revealed the crucial roles of CX3CL1-CX3CR1 axis in skin wound healing. Although repeated wounds frequently develop into skin cancer, the roles of CX3CL1 in skin carcinogenesis remain elusive. Here, we proved that CX3CL1 protein expression and CX3CR1+ macrophages were observed in human skin cancer tissues. Similarly, we observed the enhancement of CX3CL1 expression and the abundant accumulation of CX3CR1+ tumor-associated macrophages (TAMs) with M2 phenotypes in the skin carcinogenesis process induced by the combined treatment with 7,12-dimethylbenz-(a)anthracene (DMBA) and 12-O-tetradecanoylphorbol-13-acetate (TPA). In this mouse skin carcinogenesis process, CX3CR1+ TAMs exhibited M2 phenotypes with the expression of Wnt3a and angiogenic molecules including vascular endothelial growth factor (VEGF) and matrix metalloproteinase (MMP)-9. Compared to wild-type mice, CX3CR1-deficient mice showed fewer numbers of skin tumors with a lower incidence. Concomitantly, M2-macrophage numbers and neovascularization reduced with the depressed expression of angiogenic factors and Wnt3a. Thus, the CX3CL1-CX3CR1 axis can crucially contribute to skin carcinogenesis by regulating the accumulation and functions of TAMs. Thus, this axis can be a good target for preventing and/or treating skin cancers.

1930: Integrative analysis of multi-platform reverse-phase protein array data for the pharmacodynamic assessment of response to targeted therapies
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Posted to bioRxiv 16 Sep 2019

Integrative analysis of multi-platform reverse-phase protein array data for the pharmacodynamic assessment of response to targeted therapies
76 downloads cancer biology

Adam Byron, Stephan Bernhardt, Bérengère Ouine, Aurélie Cartier, Kenneth G. Macleod, Neil Carragher, Vonick Sibut, Ulrike Korf, Bryan Serrels, Leanne de Koning

Reverse-phase protein array (RPPA) technology uses panels of high-specificity antibodies to measure proteins and protein post-translational modifications in cells and tissues. The approach offers sensitive and precise quantification of large numbers of samples and has thus found applications in the analysis of clinical and pre-clinical samples. For effective integration into drug development and clinical practice, robust assays with consistent results are essential. Leveraging a collaborative RPPA model, we set out to assess the variability between three different RPPA platforms using distinct instrument set-ups and workflows. Employing multiple RPPA-based approaches operated across distinct laboratories, we characterised a range of human breast cancer cells and their protein-level responses to two clinically relevant cancer drugs. We integrated multi-platform RPPA data and used unsupervised learning to identify protein expression and phosphorylation signatures that were not dependent on RPPA platform and analysis workflow. Our findings indicate that proteomic analyses of cancer cell lines using different RPPA platforms can identify concordant profiles of response to pharmacological inhibition, including when using different antibodies to measure the same target antigens. These results highlight the robustness and the reproducibility of RPPA technology and its capacity to identify protein markers of disease or response to therapy.

1931: Epigenetic regulation of protein translation in KMT2A-rearranged AML
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Posted to bioRxiv 02 Oct 2019

Epigenetic regulation of protein translation in KMT2A-rearranged AML
76 downloads cancer biology

Alexandra Lenard, Hongbo Michael Xie, Simone S Riedel, Zuo-Fei Yuan, Nan Zhu, Tobias Neff, Kathrin Maria Bernt

Inhibition of the histone methyl-transferase DOT1L (KMT4) has shown encouraging activity in preclinical models of KMT2A (MLL)-rearranged leukemia. The DOT1L inhibitor pinometostat (EPZ5676) was well tolerated in early phase clinical trials and showed modest clinical activity, including occasional complete responses (CRs) as single agent. These studies support the development of combinatorial therapies for KMT2A-rearranged leukemias. Here, we investigated two novel combinations: dual inhibition of the histone methyltransferases DOT1L and EZH2, and the combination of a DOT1L inhibitor with the protein synthesis inhibitor homoharringtonine (HHR). EZH2 is the catalytic histone methyltransferase in the polycomb repressive complex 2 (PRC2), and inhibition of EZH2 has reported preclinical activity in KMT2A-rearranged leukemia. We found that the H3K79 and H3K27 methyl marks are not dependent on each other, and that DOT1L and EZH2 inhibition affect largely distinct gene expression programs. In particular, the KMT2A/DOT1L target HOXA9, which is commonly de-repressed as a consequence of PRC2 loss or inhibition in other contexts, was not re-activated upon dual DOT1L/EZH2 knockout or inhibition. Despite encouraging data in murine KMT2A-MLLT3 transformed cells suggesting synergy between DOT1L and EZH2 inhibition, we found both synergistic and antagonistic effects on a panel of human KMT2A rearranged cell lines. Combinatorial inhibition of DOT1L and EZH2 is thus not a promising strategy. We identified opposing effects on ribosomal gene transcription and protein translation by DOT1L and EZH2 as a mechanism that is partially responsible for observed antagonistic effects. The effects of DOT1L inhibition on ribosomal gene expression prompted us to evaluate the combination of EPZ5676 with a protein translation inhibitor. EPZ5676 was synergistic with the protein translation inhibitor homoharringtonine (HHR), supporting further preclinical/clinical development of this combination.

1932: Single cell genomic characterization reveals the cellular reprogramming of the gastric tumor microenvironment
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Posted to bioRxiv 01 Oct 2019

Single cell genomic characterization reveals the cellular reprogramming of the gastric tumor microenvironment
76 downloads cancer biology

Anuja Sathe, Sue Grimes, Billy T. Lau, Jiamin Chen, Carlos Suarez, Robert Huang, George Poultsides, Hanlee Ji

Purpose: The tumor microenvironment (TME) consists of a heterogenous cellular milieu that can influence cancer cell behavior. The characteristics of the cellular TME have a dramatic impact on treatments such as immunotherapy. These features can be revealed with single-cell RNA sequencing (scRNA-seq). We hypothesized that single cell gene expression studies of gastric cancer (GC) together with paired normal tissue and peripheral blood mononuclear cells (PBMCs) would identify critical elements of cellular dysregulation not apparent with other approaches. Methods: Single cell gene expression studies were conducted on seven patients with GC and one patient with intestinal metaplasia. We sequenced 56,167 cells comprising GC (32,407 cells), paired normal tissue (18,657 cells) and PBMCs (5,103 cells). Protein expression of genes of interest was validated by multiplex immunofluorescence. Results: Tumor epithelium had copy number alterations and a distinct gene expression program compared to normal with intra-tumor heterogeneity. The GC TME was significantly enriched for stromal cells, macrophages, dendritic cells (DCs) and Tregs. TME-exclusive stromal cells expressed extracellular matrix components distinct from normal tissue. Macrophages were transcriptionally heterogenous and did not conform to a binary M1/M2 paradigm. Gene expression program of tumor DCs was unique from PBMC DCs. TME-specific cytotoxic T cells comprised of two exhausted heterogenous subsets. Helper, cytotoxic T, Treg and NK cells expressed multiple immune checkpoint or costimulatory molecules. Receptor-ligand analysis revealed TME-exclusive inter-cellular communication.

1933: Mechanistic and compositional studies of the autophagy-inducing areca nut ingredient
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Posted to bioRxiv 20 Jun 2019

Mechanistic and compositional studies of the autophagy-inducing areca nut ingredient
76 downloads cancer biology

Chang-Ta Chiu, Shyun-Yeu Liu, Ching-Yu Yen, Meng-Ting Tsai, Huei-Cih Chang, Young-Chau Liu, Mei-Huei Lin

Areca nut (AN) is a popular chewing carcinogen worldwide causing a variety of diseases such as oral and esophageal carcinomas. We previously found that the partially purified 30-100 kDa fraction of AN extract (ANE 30-100K) induces autophagy in oral carcinoma OECM-1 cells and some other different types of cells. Since autophagy is known to play important roles in tumor establishment and development, the underlying mechanisms of ANE 30-100K-induced autophagy (AIA) is worthy of further investigation. In this study, we further demonstrated that the cytotoxic concentration of ANE 30-100K induces some typical autophagy hallmarks in esophageal carcinoma (CE81T/VGH) cells in an Atg5-dependent manner. Furthermore, the endocytosis inhibitor (methyl-β-cyclodextrin) and two caveolin shRNAs, as well as two proteasome inhibitors (lactacystin and epoxomicin), were shown to attenuate ANE 30-100K-induced cytotoxicity and LC3-II accumulation significantly in OECM-1 and CE81T/VGH cells. Finally, we also analyzed the carbohydrate compositions of ANE 30-100K by phenol-sulfuric acid method and high performance anion exchange chromatography with pulse amperic detector. The results showed that ANE 30-100K contains about 67% carbohydrate and is composed of fucose (5.938%), arabinose (24.631%), glucosamine (8.066%), galactose (26.820%), glucose (21.388%), and mannose (13.157%). Collectively, these results suggest that caveolin-mediated endocytosis and proteasome are required for AIA and the major components of ANE 30-100K are carbohydrates. This study may have provided new knowledges of the action mechanisms and compositions of ANE 30-100K.

1934: Differential antitumor activity of compounds targeting the ubiquitin-proteasome machinery in gastrointestinal stromal tumors (GIST)
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Posted to bioRxiv 04 Oct 2019

Differential antitumor activity of compounds targeting the ubiquitin-proteasome machinery in gastrointestinal stromal tumors (GIST)
75 downloads cancer biology

Jessica L Rausch, Areej A Ali, Donna M Lee, Yemarshet K Gebreyohannes, Keith R Mehalek, Aya Agha, Sneha S Patil, Yanis Tolstov, Jasmien Wellens, Harbir S Dhillon, Kathleen R Makielski, Maria Debiec-Rychter, Patrick Schoeffski, Agnieszka Wozniak, Anette Duensing

The majority of gastrointestinal stromal tumors (GISTs) are driven by oncogenic KIT signaling and can therefore be effectively treated with the tyrosine kinase inhibitor (TKI) imatinib mesylate. However, most GISTs develop imatinib resistance through secondary KIT mutations. The type of resistance mutation determines sensitivity to approved second-/third-line TKIs but can show high inter- and intratumoral heterogeneity. Therefore, therapeutic strategies that target KIT independently of the mutational status are intriguing. Inhibiting the ubiquitin-proteasome machinery with bortezomib is effective in GIST cells through a dual mechanism of KIT transcriptional downregulation and upregulation of the pro-apoptotic histone H2AX but clinically problematic due to the drugs adverse effects. We therefore tested second-generation inhibitors of the 20S proteasome (delanzomib, carfilzomib and ixazomib) with better pharmacologic profiles as well as compounds targeting regulators of ubiquitination (b-AP15, MLN4924) for their effectiveness and mechanism of action in GIST. All three 20S proteasome inhibitors were highly effective in vitro and in vivo, including in imatinib-resistant models. In contrast, b-AP15 and MLN4924 were only effective at high concentrations or had mostly cytostatic effects, respectively. Our results confirm 20S proteasome inhibitors as promising strategy to overcome TKI resistance in GIST, while highlighting the complexity of the ubiquitin-proteasome machinery as therapeutic target.

1935: Predicting Primary Site of Secondary Liver Cancer with a Neural Estimator of Metastatic Origin (NEMO)
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Posted to bioRxiv 02 Jul 2019

Predicting Primary Site of Secondary Liver Cancer with a Neural Estimator of Metastatic Origin (NEMO)
75 downloads cancer biology

Geoffrey F. Schau, Erik A. Burlingame, Guillaume Thibault, Tauangtham Anekpuritanang, Ying Wang, Joe W. Gray, Christopher Corless, Young Hwan Chang

Pathologists rely on clinical information, tissue morphology, and sophisticated molecular diagnostics to accurately infer the metastatic origin of secondary liver cancer. In this paper, we introduce a deep learning approach to identify spatially localized regions of cancerous tumor within hematoxylin and eosin stained tissue sections of liver cancer and to generate predictions of the cancer’s metastatic origin. Our approach achieves an accuracy of 90.2% when classifying metastatic origin of whole slide images into three distinct classes, which compares favorably to an established clinical benchmark by three board-certified pathologists whose accuracies ranged from 90.2% to 94.1% on the same prediction task. This approach illustrates the potential impact of deep learning systems to leverage morphological and structural features of H&E stained tissue sections to guide pathological and clinical determination of the metastatic origin of secondary liver cancers.

1936: Different localization of fluorescently labeled N- and C-termini of nucleolin variants in human glioblastoma cell culture
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Posted to bioRxiv 02 Apr 2019

Different localization of fluorescently labeled N- and C-termini of nucleolin variants in human glioblastoma cell culture
75 downloads cancer biology

Dmitri Panteleev, Nikolai Pustogarov, Alexandr Revishchin, Dzhirgala Shamadykova, Sergey Drozd, Sergey Goryanov, Alexander Potapov, Galina Pavlova

Nucleolus-oriented protein nucleolin plays a significant role in the life of a normal mammalian cell. However, nucleolin is also actively expressed in cells of malignant tumors. At the same time, its expression in different types of cancer is significantly increased compared with normal cells. It is interesting that nucleolin localization often varies in tumor cells, namely in the cytoplasm and on the cell membrane. This fact is considered to be a poor prognostic indicator. This work is devoted to the study of the distribution of nucleolin in human glioblastoma cells. Glioblastoma is one of the most aggressive malignant tumors with an absolutely unfavorable prognosis. These tumors have a high proliferative potential, but in addition they are often characterized by invasive properties. Research on lineage cells does not let to fully study these properties of glioblastoma, since lineage cells are very different from the actual tumor. In our study, we used two primary cell cultures of human glioblastoma with varying degrees of invasiveness of the original tumors. The main interest was directed at studying the localization of nucleolin and its correlation with the invariability of the N- and C-termini of the corresponding protein. Particular attention was paid to the significance of the unaltered C-terminus of nucleolin for its distribution in the cells of transplanted human glioblastoma cultures derived from patient tissues. The aim of this work is to find the relationship between the deformation of the N- or C-terminal sequences of nucleolin and its localization.We showed that in glioblastoma cells, with a high degree of invasion, nucleolin is found in the cytoplasm and close to the cell membrane, and the distribution of nucleolin with undeformed C and N-terminal does not match.

1937: PD-L1 expression in 522 selected sarcomas with subset analysis of recurrent or metastatic matched samples and association with tumour-infiltrating lymphocytes
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Posted to bioRxiv 04 Sep 2019

PD-L1 expression in 522 selected sarcomas with subset analysis of recurrent or metastatic matched samples and association with tumour-infiltrating lymphocytes
74 downloads cancer biology

Ana Cristina Vargas, Fiona M Maclean, Loretta Sioson, Dinh Tran, Fiona Bonar, Annabelle Mahar, Alison L Cheah, Peter Russell, Peter Grimison Peter Grimison, Louise Richardson Louise Richardson, Anthony J Gill

We assessed the frequency of programmed death-ligand 1 (PD-L1) expression by immunohistochemistry (IHC) in a cohort of 522 sarcomas from 457 patients, incuding a subset of 46 patients with 63 matched samples from local recurrence or metastases with primary tumours and/or metachronous metastases. We also investigated the correlation of PD-L1 with the presence and degree of tumour-infiltrating lymphocytes (TILs) in a subset of cases. IHC was performed using the PD-L1 SP263 companion kit (VENTANA) on tissue microarrays from an archival cohort. Evaluation of PD-L1 and TILs was performed on full sections for a subset of 23 cases. Fisher’s exact and Mann Whitney test were used to establish significance (P <0.05). PD-L1 positive expression (≥1%) was identified in 31% of undifferentiated pleomorphic sarcomas, 29% of angiosarcomas, 26% of rhabdomyosarcomas, 18% of myxofibrosarcomas, 11% of leiomyosarcomas and 10% of dedifferentiated liposarcomas. Negative expression was present in all atypical lipomatous tumous/well-differentiated lipoasarcomas, myxoid liposarcomas, synovial sarcomas, pleomorphic liposarcomas, and Ewing sarcomas. PD-L1 IHC was concordant in 81% (38 of 47) of matched/paired samples. PD-L1 IHC was discordant in 19% (9 of 47 matched/paired samples), displaying differences in the proportion of cells expressing PD-L1 amongst paired samples with the percentage of PD-L1-positive cells increasing in the metastatic/recurrent site compared to the primary in 6 of 9 cases (67%). Significant correlation between PD-L1 expression and the degree of TILs was exclusively identified in the general cohort of leiomyosarcomas, but not in other sarcoma subtypes or in metastatic/recurrent samples. We conclude that the prevalence of PD-L1 expression in selected sarcomas is variable and likely to be clone dependent. Importantly, we demonstrated that PD-L1 can objectively increase in a small proportion of metastases/recurrent sarcomas, offering the potential of treatment benefit to immune checkpoint inhibitors in this metastatic setting.

1938: Large-scale pan-cancer analysis reveals broad prognostic association between TGF-β ligands, not Hedgehog, and GLI1/2 expression in tumors
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Posted to bioRxiv 08 Aug 2019

Large-scale pan-cancer analysis reveals broad prognostic association between TGF-β ligands, not Hedgehog, and GLI1/2 expression in tumors
73 downloads cancer biology

Aurélien de Reyniès, Delphine Javelaud, Nabila Elarouci, Véronique Marsaud, Cristèle Gilbert, Alain Mauviel

GLI1 expression is broadly accepted as a marker of Hedgehog pathway activation in tumors. Efficacy of Hedgehog inhibitors is essentially limited to tumors bearing activating mutations of the pathway. GLI2, a critical Hedgehog effector, is necessary for GLI1 expression and is a direct transcriptional target of TGF-β/SMAD signaling. We examined the expression correlations of GLI1/2 with TGFB and HH genes in 152 distinct transcriptome datasets totaling over 23,500 patients and representing 37 types of neoplasms. Their prognostic value was measured in over 15,000 clinically annotated tumor samples from 26 tumor types. In most tumor types, GLI1 and GLI2 follow a similar pattern of expression and are equally correlated with HH and TGFB genes. However, GLI1/2 broadly share prognostic value with TGFB genes and a mesenchymal/EMT signature, not with HH genes. Our results provide a likely explanation for the frequent failure of anti-Hedgehog therapies in tumors, as they suggest a key role for TGF-β, not Hedgehog, ligands, in tumors with elevated GLI1/2-expression.

1939: Dietary sulfate-driven and gut dysbiosis-triggered breast cancer-related gene upregulation
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Posted to bioRxiv 10 Oct 2018

Dietary sulfate-driven and gut dysbiosis-triggered breast cancer-related gene upregulation
73 downloads cancer biology

CHEN YanPingf, LIAO Tao, TAN LiLi, CHEN DongMei, XU Qin, Song JianPing, ZHEN QingPing

By gut microbiota metagenomic analysis, we found that the abundance of sulfatase-secreting bacteria (SSB) in the gut of mice fed chondroitin sulfate (CS) increases with significant individual difference. The fluctuation of lipopolysaccharide (LPS) and pro-inflammatory indicators with significant individual and tissue variations was also observed. After mice were fed mixed with CS or injected separately with LPS, the breast cancer-related transcriptional factor genes, BCL11A and RUNX1, were upregulated, whereas the tumor suppressor gene, TP53BP1, were downregulated. Further, the mammary myopithelium marker CK5/6, the mammary hyperplasia marker Ki-67, and other tumor markers were also upregulated. While the exogenous estradiol does not induce the expression of BCL11A, RUNX1, and TP53BP1, the estrogen receptor (ER) agonist Fulvestrant that mimics estradiol action not only elevates estradiol concentrations, but also upregulates tumor marker expression levels, revealing that ER inflammatory inactivation and hyperestrogenemia induction might be the etiological cues of breast cancer origin. This study has preliminarily established a possible correlation of gut microbiota dysbiosis and chronic low-grade inflammation with the early-phase onset of breast cancer in mice. The statistical insignificance of test data was attributed to the individual difference of gut microbiota compositions, which determining the individual and tissue variations of systemic inflammation.

1940: Loss of the Krüppel-like factor 4 tumor suppressor is associated with epithelial-mesenchymal transition in colorectal cancer
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Posted to bioRxiv 22 Aug 2019

Loss of the Krüppel-like factor 4 tumor suppressor is associated with epithelial-mesenchymal transition in colorectal cancer
72 downloads cancer biology

Kimberley C Agbo, Jessie Z Huang, Amr M Ghaleb, Jennie L Williams, Kenneth R Shroyer, Agnieszka B Bialkowska, Vincent W Yang

Colorectal cancer (CRC) is the third leading cancer-related cause of death due to its propensity to metastasize. Epithelial-mesenchymal transition (EMT) is a multistep process important for invasion and metastasis of CRC. Krüppel-like factor 4 (KLF4) is a zinc finger transcription factor highly expressed in differentiated cells of the intestinal epithelium. KLF4 has been shown to play a tumor suppressor role during CRC tumorigenesis - its loss accelerates development and progression of cancer. The present study examines the relationship between KLF4 and markers of EMT in CRC. Methods: Immunofluorescence staining for KLF4 and EMT markers was performed on archived patient samples after colorectal cancer resection and on colonic tissues of mice with colitis-associated cancer. Results: We found that KLF4 expression is lost in tumor sections obtained from CRC patients and in those of mouse colon following azoxymethane and dextran sodium sulfate (AOM/DSS) treatment when compared to their respective normal appearing mucosa. Importantly, in CRC patient tumor sections we observed a negative correlation between KLF4 levels and mesenchymal markers including TWIST, β-catenin, claudin-1, N-cadherin, and vimentin. Similarly, in tumor tissues from AOM/DSS-treated mice KLF4 levels were negatively correlated with mesenchymal markers including SNAI2, β-catenin, and vimentin and positively correlated with the epithelial marker E-cadherin. Conclusion: These findings suggest that the loss of KLF4 expression is a potentially significant indicator of EMT in CRC.

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