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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 84,482 bioRxiv papers from 363,659 authors.

Most downloaded bioRxiv papers, all time

in category cancer biology

2,901 results found. For more information, click each entry to expand.

1921: C. elegans models of Marfan and Marfan-like Syndromes reveal trafficking defects of the type II TGFβ receptor as a potential novel disease mechanism
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Posted to bioRxiv 03 Dec 2018

C. elegans models of Marfan and Marfan-like Syndromes reveal trafficking defects of the type II TGFβ receptor as a potential novel disease mechanism
239 downloads cancer biology

Jing Lin, Mehul Vora, Nanci S Kane, Ryan J Gleason, Richard W Padgett

The article has been withdrawn by the authors due to concerns from one of the authors regarding information being available prior to publication. Therefore, the authors do not wish this work to be cited as reference for the project.

1922: Identifying conserved molecular targets required for cell migration of glioblastoma cancer stem cells
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Posted to bioRxiv 13 Jun 2019

Identifying conserved molecular targets required for cell migration of glioblastoma cancer stem cells
239 downloads cancer biology

Josephine Volovetz, Artem D Berezovsky, Tyler Alban, Yujun Chen, George F. Aranjuez, Ashley Burtscher, Kelly Shibuya, Daniel J. Silver, John Peterson, Danny Manor, Jocelyn A. McDonald, Justin Lathia

Glioblastoma (GBM) is the most prevalent primary malignant brain tumor and is associated with extensive tumor cell infiltration into the adjacent brain parenchyma. However, there are limited targeted therapies that address this disease hallmark. While the invasive capacity of self-renewing cancer stem cells (CSCs) and their non-CSC progeny has been investigated, the mode(s) of migration used by CSCs during invasion is currently unknown. Here we used time-lapse microscopy to evaluate the migratory behavior of CSCs, with a focus on identifying key regulators of migration. A head-to-head migration assay demonstrated that CSCs are more invasive than non-CSCs. Time-lapse live cell imaging further revealed that GBM patient-derived CSC models either migrate in a collective manner or in a single cell fashion. To uncover conserved molecular regulators responsible for collective cell invasion, we utilized the genetically tractable Drosophila border cell collective migration model. Candidates for functional studies were generated using results from a targeted Drosophila genetic screen followed by gene expression analysis of the human homologs in GBM tumors and associated GBM patient prognosis. This strategy identified the highly conserved small GTPase, Rap1a, as a potential regulator of cell invasion. Alteration of Rap1a activity impaired the forward progress of Drosophila border cells during development. Rap1a expression was elevated in GBM and associated with higher tumor grade. Functionally, the levels of activated Rap1a impacted CSC migration speed out of spheres onto extracellular matrix. The data presented here demonstrate that CSCs are more invasive than non-CSCs, are capable of both collective and single cell migration, and express conserved genes that are required for migration and invasion. Using this integrated approach, we identified a new role for Rap1a in the migration of GBM CSCs.

1923: Disseminating cells in human tumours acquire an EMT stem cell state that is predictive of metastasis
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Posted to bioRxiv 08 Apr 2020

Disseminating cells in human tumours acquire an EMT stem cell state that is predictive of metastasis
239 downloads cancer biology

Gehad Youssef, Luke Gammon, Leah Ambler, Bethan Wicker, Swatisha Patel, Hannah Cottom, Kim Piper, Ian C Mackenzie, Michael P Philpott, Adrian Biddle

Cancer stem cells undergo epithelial-mesenchymal transition (EMT) to drive metastatic dissemination in experimental cancer models. However, tumour cells undergoing EMT have not been observed disseminating into the tissue surrounding human tumour specimens, leaving the relevance to human cancer uncertain. Here, we identify an EMT stem cell state that retains EpCAM and CD24 after undergoing EMT and exhibits enhanced plasticity. This afforded the opportunity to investigate whether retention of EpCAM and CD24 alongside upregulation of the EMT marker Vimentin can identify disseminating EMT stem cells in human oral cancer specimens. Examining disseminating tumour cells in the stromal region of 3500 imaging fields from 24 human oral cancer specimens, evenly divided into metastatic and non-metastatic specimens, we see a significant enrichment of EpCAM, CD24 and Vimentin co-stained cells in metastatic specimens. Through training an artificial neural network on the EpCAM, CD24 and Vimentin co-staining, we predict metastasis with high accuracy (F1 0.91; AUC 0.87). We have observed, for the first time, disseminating EMT stem cells in patient histological specimens and demonstrated their utility for predicting metastatic disease.

1924: Anti-tumor effects of an Id antagonist with no acquired resistance
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Posted to bioRxiv 06 Jan 2020

Anti-tumor effects of an Id antagonist with no acquired resistance
239 downloads cancer biology

Paulina M Wojnarowicz, Marta Garcia Escolano, Yun-Han Huang, Bina Desai, Yvette Chin, Riddhi Shah, Sijia Xu, Ouathek Ouerfelli, Rajesh Kumar Soni, John Philip, David C Montrose, John H Healey, Vinagolu K Rajasekhar, William A Garland, Larry Norton, Neal Rosen, Ronald C. Hendrickson, Xi Kathy Zhou, Antonio Iavarone, Joan Massague, Andrew J Dannenberg, Anna Lasorella, Robert Benezra

Id proteins are helix-loop-helix (HLH) transcriptional regulators frequently overexpressed in cancer. Id proteins inhibit basic HLH transcription factors through protein-protein interactions, often inhibiting differentiation and sustaining proliferation. We recently identified a small-molecule, AGX51, which targets Id proteins for degradation and impairs ocular neovascularization in mouse models. Here we show that AGX51 treatment of cancer cell lines impaired cell growth and viability that results from a dramatic increase in ROS production upon Id degradation. In mouse models, AGX51 treatment suppressed breast cancer colonization in the lung, regressed the growth of paclitaxel-resistant breast tumors when combined with paclitaxel and reduced tumor burden in a model of sporadic colorectal neoplasia. Furthermore, in cells and mice, we failed to observe acquired resistance to AGX51 likely the result of the immutability of the binding pocket and efficient degradation of the Id proteins. Thus, AGX51 is a first-in-class compound that antagonizes Id proteins, shows strong anti-tumor effects and may be further developed for the management of multiple cancers.

1925: Lymphatic metastases have more diverse roots than distant metastases
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Posted to bioRxiv 02 Nov 2019

Lymphatic metastases have more diverse roots than distant metastases
239 downloads cancer biology

Johannes G. Reiter, Shriya Nagpal, Kamila Naxerova

Both lymphatic and distant metastases arise through cancer cell migration and colonization of ectopic sites. Nonetheless, the two metastasis types are associated with significantly different clinical outcomes, suggesting that distinct biological mechanisms may drive their formation. Here we show fundamental differences in the seeding patterns of lymphatic and distant metastases. Analyzing the reconstructed phylogenies of human colorectal cancers, we find that distant metastases typically are monophyletic, originating from one common ancestor. Lymphatic metastases, in contrast, are almost exclusively polyphyletic and can be seeded from many primary tumor regions. We develop a rigorous mathematical framework for quantifying the phylogenetic diversity of metastases while accounting for differential lesion sampling among patients. Our results indicate that a smaller fraction of primary tumor cells gives rise to distant metastases than lymphatic metastases. Thus, the two metastasis types exhibit profoundly distinct phylogenetic traits, indicating that different evolutionary mechanisms may drive their formation and influence their clinical behavior.

1926: Altering microtubule dynamics is synergistically toxic with inhibition of the spindle checkpoint
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Posted to bioRxiv 22 Jul 2019

Altering microtubule dynamics is synergistically toxic with inhibition of the spindle checkpoint
239 downloads cancer biology

Klaske M. Schukken, Yi-Chih Lin, Michael Schubert, Stephanie F. Preuss, Judith E Simon, Hilda van den Bos, Zuzana Storchova, Maria Colome-Tatche, Holger Bastians, Diana C.J. Spierings, Floris Foijer

Chromosome instability (CIN) and aneuploidy are hallmarks of cancer. As the majority of cancers are aneuploid, targeting aneuploidy or CIN may be an effective way to target a broad spectrum of cancers. Here, we perform two small molecule compound screens to identify drugs that selectively target cells that are aneuploid or exhibit a CIN phenotype. We find that aneuploid cells are much more sensitive to the energy metabolism regulating drug ZLN005 than their euploid counterparts. Furthermore, cells with an ongoing CIN phenotype, induced by spindle assembly checkpoint (SAC) alleviation, are significantly more sensitive to the Src kinase inhibitor SKI606. We show that inhibiting Src kinase increases microtubule polymerization rates and, more generally, that deregulating microtubule polymerization rates is particularly toxic to cells with a defective SAC. Our findings therefore suggest that tumors with a dysfunctional SAC are particularly sensitive to microtubule poisons and, vice versa, that compounds alleviating the SAC provide a powerful means to treat tumors with deregulated microtubule dynamics.

1927: Fucosyltransferase 4 shapes oncogenic glycoproteome to drive metastasis of lung adenocarcinoma
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Posted to bioRxiv 02 Sep 2019

Fucosyltransferase 4 shapes oncogenic glycoproteome to drive metastasis of lung adenocarcinoma
239 downloads cancer biology

Hsuan-Hsuan Lu, Shu-Yung Lin, Rueyhung R. Weng, Yi-Hsiu Juan, Yen-Wei Chen, Hsin-Han Hou, Zheng-Ci Hung, Giovanni Audrey Oswita, Yi-Jhen Huang, Jin-Yuan Shih, Chong-Jen Yu, Hsing-Chen Tsai

Aberrant fucosylation plays a critical role in lung cancer progression. Identification of the key fucosyltransferase as a therapeutic target may refine lung cancer management. Here, we identified a terminal α1,3-fucosyltransferase, FUT4, as the key prognostic predictor for lung adenocarcinoma through transcriptomic screens in lung cancer cohorts. Overexpression of FUT4 promotes lung cancer invasion, migration and cell adhesion in vitro and provokes distant metastases in mouse xenograft models. RNA-seq and glycoproteomics analyses revealed that FUT4 mediates aberrant fucosylation of intracellular transport and signal transduction proteins, which facilitates concurrent transcriptional activation of multiple cellular processes, including membrane trafficking, cell cycle, and major oncogenic signaling pathways. Notably, knockdown of FUT4 markedly curtailed lung colonization and distant metastases of lung cancer cells in mouse xenograft models. In addition, the metastatic phenotype provoked by FUT4-mediated fucosylproteomic networks can be diminished by targeted pathway inhibitors. Collectively, FUT4 represents a promising therapeutic target in lung cancer metastasis. Our data highlight the potentials for integration of glycomics into precision medicine-based therapeutics.

1928: The large GTPase, mGBP-2, regulates Rho family GTPases to inhibit migration and invadosome formation in Triple-Negative Breast Cancer cells.
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Posted to bioRxiv 21 Jun 2019

The large GTPase, mGBP-2, regulates Rho family GTPases to inhibit migration and invadosome formation in Triple-Negative Breast Cancer cells.
238 downloads cancer biology

Geoffrey O Nyabuto, John P Wilson, Samantha A Heilman, Ryan C Kalb, Ankita V Abnave, Deborah J. Vestal

Breast cancer is the most common cancer in women. Despite advances in early detection and treatment, it is predicted that over 40,000 women will die of breast cancer in 2019. This number of women is still too high. To lower this number, more information about the molecular players in breast cancer are needed. Several members of the Guanylate-Binding Proteins (GBPs) have been correlated with better prognosis in breast cancer. In this study, we asked if the expression of GBP-2 in breast cancer merely provided a biomarker for improved prognosis or whether it actually contributed to improving outcome. Specifically, we asked whether murine GBP-2 exhibited cell autonomous behavior that altered breast cancer cells in a manner predicted to improve prognosis. To answer this, the 4T1 model of murine Triple-Negative Breast Cancer was used. 4T1 cells themselves are highly aggressive and highly metastatic, while 67NR cells, isolated from the same tumor, do not leave the primary site. mGBP-2 did not alter cell proliferation in these two cell lines, but mGBP-2 expression inversely correlated with migration. More specifically, mGBP-2 inhibits cell migration and invadopodia formation by inhibiting the activation of Rac1, while promoting the activation of CDC42 and RhoA. Together these data demonstrate that mGBP-2 is responsible for cell autonomous activities that make breast cancer cells less aggressive.

1929: Androgen Receptor-Induced Integrin α6β1 and Adhesion to Laminin Promotes Survival and Drug Resistance in Castration-Resistant Prostate Cancer through BNIP3
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Posted to bioRxiv 15 Jun 2018

Androgen Receptor-Induced Integrin α6β1 and Adhesion to Laminin Promotes Survival and Drug Resistance in Castration-Resistant Prostate Cancer through BNIP3
238 downloads cancer biology

Eric A Nollet, Sourik S Ganguly, Veronique V. Schulz, Anne Cress, Cindy K Miranti

Although castration-resistant prostate cancers no longer respond to anti-androgen therapies, the androgen receptor (AR) is still required to promote tumor survival. However, the signaling pathways downstream of AR that promote this survival are not well known. We recently identified an AR-dependent survival pathway whereby AR induction of integrin α6β1 and adhesion to laminin activates NF-κB/RelA signaling and Bcl-xL. This pathway acts in parallel with the PI3K/Akt pathway in Pten-null tumor cells such that combined inhibition of both PI3K and integrin α6β1 is required to kill tumor cells adherent to laminin. However, PTEN-null castration-resistant tumors were not effectively inhibited by this combination. We discovered that BNIP3, a hypoxia-induced BH3-only, pro-mitophagic Bcl2 family member, is induced by androgen in castration-resistant cells through integrin α6β1 signaling to HIF1α. Furthermore, castration-resistant cells adherent to laminin were much more efficient at inducing autophagy in response to androgen. Androgen blocked the ability of the PI3K inhibitor PX-866 to kill castration-resistant tumors, but this was reversed by loss of BNIP3. Although BNIP3 was dispensable for androgen-induced autophagy, its mitophagy function was required for BNIP3 to promote resistance to PI3K inhibition. Thus, adhesion to laminin triggers signaling through AR/α6β1/HIF1α in castration-resistant cells to drive the expression of BNIP3 and cooperates with AR/α6β1-mediated autophagy, both of which contribute to PI3K resistance through induction of mitophagy.

1930: Nitric oxide-dependent inflammation underlies Notch and PI3K/Akt oncogene cooperation
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Posted to bioRxiv 09 Aug 2017

Nitric oxide-dependent inflammation underlies Notch and PI3K/Akt oncogene cooperation
238 downloads cancer biology

Santiago Nahuel Villegas, Rita Gombos, Irene Gutiérrez Pérez, Lucia García López, Jesús García-Castillo, Diana Marcela Vallejos, Vanina Da Ros, József Mihály, Maria Dominguez

Concurrent activating mutations of the Notch and PI3K/Akt signalling pathways cooperate in the induction of aggressive cancers. Unfortunately, direct targeting of any of these aberrant pathways can result in severe side effects due to their broad physiological roles in multiple organs. Here, using an unbiased chemical in vivo screen in Drosophila we identified compounds that suppress the activity of the pro-inflammatory enzymes, nitric oxide synthase (NOS) and lipoxygenase (LOX), capable to block oncogenic Notch-PI3K/Akt cooperation without unwanted side effects. Genetic inactivation of NOS and LOX signalling components mirrors the anti-tumorigenic effect of the hit compounds. We show that NOS activity and immunosuppression associated to inflammation facilitates Notch-mediated tumorigenesis. Our study reveals an unnoticed immune inflammatory process underlying Notch-PI3K/Akt tumours and exposes NOS as a druggable target for anti-cancer therapeutic development.

1931: Imprint of parity and age at first birth on the genomic landscape of subsequent breast cancer
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Posted to bioRxiv 27 Jun 2018

Imprint of parity and age at first birth on the genomic landscape of subsequent breast cancer
238 downloads cancer biology

Bastien Nguyen, David Venet, Matteo Lambertini, Christine Desmedt, Roberto Salgado, Hugo Horlings, Françoise Rothé, Christos Sotiriou

Background: Although parity and age at first birth are among the most known extrinsic factors that modulates breast cancer risk, their impact on the biology of subsequent breast cancer has never been explored in depth. In this study, we investigate the imprint of parity and age at first birth on the pattern of somatic mutations, somatic copy number alterations (SCNAs), transcriptomic profiles, and tumor infiltrating lymphocytes (TILs) levels of subsequent breast cancer. Methods: A total of 313 patients with primary breast cancer with available whole genome and RNA sequencing data were included in this study. We used a multivariate analysis adjusted for age at diagnosis, pathological stage, molecular subtypes and histological subtypes. We compared nulliparous vs. parous, late parous vs. early parous, and nulliparous vs. pregnancy associated breast cancer (PABC) patients. Late and early parous patients were grouped by using the median age at first birth as a cut-off value. PABC was defined as patients diagnosed up to 10 years postpartum. Results: Genomic alterations of breast cancer are associated with age at first birth but not parity status alone. Independently of clinicopathological features, early parous patients developed tumors characterized by a higher number of Indels (Padj = 0.002), a lower frequency of CDH1 mutations (1.2% vs. 12.7%; Padj = 0.013), a higher frequency of TP53 mutations (50% vs. 22.5%; Padj = 0.010) and MYC amplification (28% vs. 7%; Padj = 0.008), and a lower prevalence of mutational signature 2. PABC were associated with increased TILs infiltration (Padj = 0.0495). Conclusions: These findings highlight an unprecedented link between reproductive history and the genomic landscape of subsequent breast cancer. With the rapid development of precision oncology, this work advocates that reproductive history should not be underestimated in future clinical studies of breast cancer.

1932: CBFβ-MYH11 interferes with megakaryocyte differentiation via modulating a gene program that includes GATA2 and KLF1
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Posted to bioRxiv 29 Oct 2018

CBFβ-MYH11 interferes with megakaryocyte differentiation via modulating a gene program that includes GATA2 and KLF1
237 downloads cancer biology

Guoqiang Yi, Amit Mandoli, Laura Jussen, Esther Tijchon, Gaëlle Cordonnier, Marten Hansen, Bowon Kim, Luan N. Nguyen, Pascal Jansen, Michiel Vermeulen, Emile van den Akker, Jonathan Bond, Joost H.A. Martens

The inv(16) acute myeloid leukemia associated CBFβ-MYH11 fusion is proposed to block normal myeloid differentiation, but whether this subtype of leukemia cells is poised for a unique cell lineage remains unclear. Here, we surveyed the functional consequences of CBFβ-MYH11 in primary inv(16) patient blasts, upon expression during hematopoietic differentiation in vitro and upon knockdown in cell lines by multi-omics profiling. Our results reveal that primary inv(16) AML cells share common transcriptomic signatures and epigenetic determiners with megakaryocytes and erythrocytes. Using in vitro differentiation systems, we reveal that CBFβ-MYH11 knockdown interferes with normal megakaryocyte maturation. Two pivotal regulators, GATA2 and KLF1, are identified to complementally occupy RUNX1 binding sites upon fusion protein knockdown, and overexpression of GATA2 partly restores megakaryocyte directed differentiation suppressed by CBFβ-MYH11. Together, our findings suggest that in inv(16) leukemia, the CBFβ-MYH11 fusion inhibits primed megakaryopoiesis by attenuating expression of GATA2/KLF1 and interfering with a balanced transcriptional program involving these two factors.

1933: CD155/CD96 promotes immunosuppression in lung adenocarcinoma (LUAD)
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Posted to bioRxiv 01 Jul 2019

CD155/CD96 promotes immunosuppression in lung adenocarcinoma (LUAD)
237 downloads cancer biology

Weiling He, Hui Zhang, Shuhua Li, Yongmei Cui, Ying Zhu, Junfeng Zhu, Yiyan Lei, Run Lin, Di Xu, Zheng Zhu, Wenting Jiang, Han Wang, Zunfu Ke

Lung adenocarcinoma (LUAD) remains one of the leading causes of death in patients with cancer. The association of CD155 with CD96 transmits an inhibitory signal and suppresses antitumor immune response. This study investigates the effect of CD155/CD96 on immune suppression in LUAD. We demonstrate that LUAD patients with high CD155 expression suffer from immune suppression and experience a poor prognosis, which coincides with an inhibited AKT-mTOR signaling pathway in CD8 T cells and subsequently up-regulated CD96 expression. Moreover, the inhibition effect can be reversed by CD96 blocking antibody. High CD155 expression inhibited the release of IFNγ from CD8 cells. Moreover, Blocking CD96 restored IFNγ production in CD8 T cells and neutralized the inhibition of IFNγ production in CD8 T cells mediated by CD155. Animal experiments showed that CD155-mediated LUAD growth might depend on its suppression antitumor immune response in the tumor microenvironment in PDX mice. In conclusion, our results suggest that LUAD cells suppress antitumor immune response in the tumor microenvironment through CD155/CD96. CD155/CD96 could be a potential therapeutic target for LUAD patients. Abbreviations LUAD: lung adenocarcinoma; IFNγ: interferon gamma; PDX: patient-derived xenograft; NSCLC: non-small cell lung cancer; PRR: poliovirus receptor–related; MDSCs: myeloid-derived suppressor cells; PRR: poliovirus receptor–related; STR: short tandem repeat; IRS: immunoreactive score; SI: staining intensity; PP: percentage of positive cells; RT-PCR: reverse transcription-polymerase chain reaction; PBS: phosphate-buffered saline; PBMCs: peripheral blood mononuclear cells; SDS–PAGE: sodium dodecyl sulfate-polyacrylamide gel electrophoresis; rCD155: recombinant human CD155; LUAD cells: lung adenocarcinoma cells; TILs: tumor-infiltrating lymphocytes; GzmB: granzyme B; IL-2 (Interleukin-2); TNF-α : tumor necrosis factor-alpha; PI: propidium Iodide; PDX: patient-derived xenograft; TIGIT: T cell immunoreceptor with Igand ITIM domains; WBC: white blood cells; MFI: mean fluorescence intensity; HPF: high power field

1934: Estrogen receptor alpha mutations in breast cancer cells cause gene expression changes through constant activity and through secondary effects
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Posted to bioRxiv 09 Apr 2020

Estrogen receptor alpha mutations in breast cancer cells cause gene expression changes through constant activity and through secondary effects
237 downloads cancer biology

Spencer Arnesen, Zannel Blanchard, Michelle M Williams, Kristofer C Berrett, Zheqi Li, Steffi Oesterreich, Jennifer K Richer, Jason Gertz

While breast cancer patients with tumors that express estrogen receptor α (ER) generally respond well to hormone therapies that block ER's actions, a significant number relapse. Approximately 30% of these recurrences harbor activating mutations in ER's ligand binding domain (LBD). ER mutations have been shown to confer ligand-independent function to ER; however, much is still unclear regarding the effect of mutant ER beyond its estrogen independence. To investigate mutant ER's molecular effects, we developed multiple isogenic ER mutant cell lines for the most common ER LBD mutations, Y537S and D538G. We found that these mutations induce differential expression of thousands of genes, the majority of which are mutant allele-specific and are not observed upon estrogen treatment of wildtype cells. The mutant-specific genes show consistent differential expression across ER mutant lines developed in other laboratories. The observed gene expression changes cannot be explained by constitutive ER activity alone, as wildtype cells with long-term estrogen exposure only exhibit some of these transcriptional changes, suggesting that mutant ER causes novel regulatory effects that are not simply due to constant activity. While ER mutations have minor effects on ER genomic binding, with the exception of ligand independence, we observed substantial differences in chromatin accessibility due to ER mutations. Mutant ER is bound to approximately a quarter of mutant-enriched accessible regions that are enriched for other DNA binding factors including FOXA1, CTCF, and OCT1. Our findings indicate that mutant ER causes several consistent effects on gene expression both indirectly and through constant activity. ### Competing Interest Statement

1935: Exosome-mediated MIR211 modulates tumor microenvironment via the DUSP6-ERK5 axis and contributes to BRAFV600E inhibitor resistance in melanoma.
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Posted to bioRxiv 13 Feb 2019

Exosome-mediated MIR211 modulates tumor microenvironment via the DUSP6-ERK5 axis and contributes to BRAFV600E inhibitor resistance in melanoma.
237 downloads cancer biology

Bongyong Lee, Anupama Sahoo, Junko Sawada, John Marchica, Sanjay Sahoo, Fabiana I. A. L. Layng, Darren Finlay, Joseph Mazar, Piyush Joshi, Masanobu Komatsu, Kristiina Vuori, Garth Powis, Petrus R. de Jong, Animesh Ray, Ranjan J Perera

The microRNA MIR211 is an important regulator of melanoma tumor cell behavior. Previous studies suggested that in certain tumors, MIR211 acted as a tumor suppressor while in others it behaved as an oncogenic regulator. When MIR211 is expressed in BRAFV600E-mutant A375 melanoma cells in mouse xenografts, it promotes aggressive tumor growth accompanied by increased cellular proliferation and angiogenesis. We demonstrate that MIR211 is transferred to adjacent cells in the tumor micro-environment via exosomes. Cross-species genome-wide transcriptomic analysis showed that human tumor-derived MIR211 interacts with the mouse transcriptome in the tumor microenvironment, and activates ERK5 signaling in human tumor cells via the modulation of a feedback loop. Human miR211 directly inhibits human DUSP6 protein phosphatase at the post-transcriptional level. We provide support for the hypothesis that DUSP6 inhibition conferred resistance of the human tumor cells to the BRAF inhibitor vemurafenib and to the MEK inhibitor cobimetinib, with associated increases in ERK5 phosphorylation. These findings are consistent with a model in which MIR211 regulates melanoma tumor proliferation and BRAF inhibitor resistance by inducing ERK5 signaling within the complex tumor microenvironment. We propose that the MIR211-ERK5 axis represents an important and sensitive regulatory arm in melanoma with potential theranostic applications.

1936: A model of Zebrafish Avatar for co-clinical trials
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Posted to bioRxiv 26 Sep 2019

A model of Zebrafish Avatar for co-clinical trials
237 downloads cancer biology

Alice Usai, Gregorio Di Franco, Patrizia Colucci, Luca Emanuele Pollina, Enrico Vasile, Niccola Funel, Matteo Palmeri, Luciana Dente, Alfredo Falcone, Luca Morelli, Vittoria Raffa

Animal “Avatars” and co-clinical trials represent an emerging concept for implementing schemes of personalized medicine in oncology. In a co-clinical trial, the cancer cells of the patient tumor are xenotransplanted in the animal Avatar for drug efficacy studies and data collected in the animal trial are used to plan the best drug treatment in the patient trial. Recently, zebrafish has been proposed for implementing Avatar models but the lack of a general criterion for chemotherapy dose conversion from humans to fishes represents a limitation for conducting co-clinical trials. Here, we validate a simple, reliant and cost-effective Avatar model based on the use of zebrafish larvae; by crossing data from safety and efficacy studies, we found a basic formula for the estimation of the dose to be used for running co-clinical trials and we validate it in a clinical study enrolling 24 adult patients with solid cancers (XenoZ, [NCT03668418][1]). [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT03668418&atom=%2Fbiorxiv%2Fearly%2F2019%2F09%2F26%2F784041.atom

1937: Background radiation impacts human longevity and cancer mortality: Reconsidering the linear no-threshold paradigm
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Posted to bioRxiv 06 Nov 2019

Background radiation impacts human longevity and cancer mortality: Reconsidering the linear no-threshold paradigm
237 downloads cancer biology

Elroei David, Marina Wolfson, Vadim E Fraifeld

The current linear-no-threshold paradigm assumes that any exposure to ionizing radiation carries some risk, thus every effort should be made to maintain the exposures as low as possible. Here, we examined whether background radiation impacts human longevity and cancer mortality. METHODS: Our data covered the entire US population of the 3139 US counties, encompassing over 320 million people. The data on background radiation levels, the average of 5-year age-adjusted cancer mortality rates, and life expectancy for both males and females in each county, was extracted using publicly available tools from official sources, and analyzed with JMP software. RESULTS: We found for the first time that life expectancy, the most integrative index of population health, was approximately 2.5 years longer in people living in areas with a relatively high vs. low background radiation (≥ 180 mrem/year and ≤ 100 mrem/year, respectively; p < 0.005; 95% confidence interval [CI]). This radiation-induced lifespan extension could to a great extent be associated with the decrease in cancer mortality rate observed for several common cancers (lung, pancreas and colon cancers for both genders, and brain and bladder cancers for males only; p < 0.05; 95% CI). CONCLUSIONS: Exposure to a high background radiation displays clear beneficial health effects in humans. These hormetic effects provide strong evidence for re-considering the linear no-threshold paradigm, at least within the natural range of low-dose radiation.

1938: Activation of TAp73 and inhibition of thioredoxin reductase for improved cancer therapy in TP53 mutant pancreatic tumors
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Posted to bioRxiv 23 Aug 2018

Activation of TAp73 and inhibition of thioredoxin reductase for improved cancer therapy in TP53 mutant pancreatic tumors
237 downloads cancer biology

Pilar Acedo, Aristi Fernandes, Joanna Zawacka-Pankau

The p73 is a tumor suppressor and belongs to the p53 family of proteins. Transcriptionally active (TA) isoform of p73 recognizes similar group of target genes with p53 and can compensate for p53 loss in inducing apoptosis in tumors in response to genotoxic stress or small-molecule treatment. Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal human cancer types. PDAC is characterized by the late onset of the disease and poor responsiveness to the existing therapies. TP53 gene mutations score second top and occur in around 75% cases. Consequently, PDAC has very low overall survival rates. Here, using drug-repurposing approach, we found that protoporphyrin IX (PpIX) and benzoporphyrin derivative monoacid ring A (BPD, verteporfin®), applied in photodynamic therapy of cancer, activate TAp73 and induce apoptosis in pancreatic cancer cells. We also found that PpIX and BPD trigger accumulation of reactive oxygen species and inhibit an antioxidant defense enzyme, thioredoxin reductase 1 (TrxR1). We demonstrated that PpIX and BPD inhibit TrxR1 both in vitro and in cells. In conclusion, our study shows that PpIX and BPD target cancer cells' vulnerabilities, namely activate TAp73 tumor suppressor and inhibit TrxR1 redox balance enzyme to overcome p53 loss. Our findings, may in future contribute to repurposing of PpIX and verteporfin® to treat pancreatic cancer patients.

1939: E2F1 Drives Breast Cancer Metastasis by Regulating the Target Gene FGF13 and Altering Cell Migration
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Posted to bioRxiv 13 Jun 2019

E2F1 Drives Breast Cancer Metastasis by Regulating the Target Gene FGF13 and Altering Cell Migration
237 downloads cancer biology

Daniel P Hollern, Matthew R Swiatnicki, Jonathan P Rennhack, Sean A Misek, Brooke C Matson, Andrew McAuliff, Kathleen A Gallo, Kathleen M Caron, Eran R. Andrechek

In prior work we demonstrated that loss of E2F transcription factors inhibits metastasis. Here we address the mechanisms for this phenotype and identify the E2F regulated genes that coordinate tumor cell metastasis. Transcriptomic profiling of E2F1 knockout tumors identified a role for E2F1 as a master regulator of a suite of pro-metastatic genes, but also uncovered E2F1 target genes with an unknown role in pulmonary metastasis. High expression of one of these genes, Fgf13, is associated with early human breast cancer metastasis in a clinical dataset. Together these data led to the hypothesis that Fgf13 is critical for breast cancer metastasis, and that upregulation of Fgf13 may partially explain how E2F1 promotes breast cancer metastasis. To test this hypothesis we ablated Fgf13 via CRISPR. Deletion of Fgf13 in a MMTV-PyMT breast cancer cell line reduces the frequency of pulmonary metastasis. In addition, loss of Fgf13 reduced in vitro cell migration, suggesting that Fgf13 may be critical for tumor cells to invade out of and escape the primary tumor. The significance of this work is twofold: we have both uncovered genomic features by which E2F1 regulates metastasis and we have identified new pro-metastatic functions for the E2F1 target gene Fgf13.

1940: Cancer cells resist mechanical destruction in the circulation via RhoA-myosin II axis
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Posted to bioRxiv 06 Apr 2019

Cancer cells resist mechanical destruction in the circulation via RhoA-myosin II axis
237 downloads cancer biology

Devon L. Moose, Benjamin L Krog, Lei Zhao, Tae-Hyung Kim, Sophia Williams-Perez, Gretchen Burke, Lillian Rhodes, Marion Vanneste, Patrick Breheny, Mohammed Milhem, Christopher S Stipp, Amy C. Rowat, Michael D Henry

During metastasis cancer cells are exposed to potentially destructive hemodynamic forces including fluid shear stress (FSS) while en route to distant sites. However, prior work indicates that cancer cells are more resistant to brief pulses of high-level fluid shear stress (FSS) in vitro relative to non-transformed epithelial cells. Herein we identify a mechanism of FSS resistance in cancer cells, and extend these findings to mouse models of circulating tumor cells (CTCs). We show that cancer cells acutely isolated from primary tumors are resistant to FSS. Our findings demonstrate that cancer cells activate the RhoA-myosin II axis in response to FSS, which protects them from FSS-induced plasma membrane damage. Moreover, we show that the myosin II activity is protective to CTCs in mouse models. Collectively our data indicate that viable CTCs actively resist destruction by hemodynamic forces and are likely to be more mechanically robust than is commonly thought.

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