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Shi B Chia, Bryan J Johnson, Junxiao Hu, Roel Vermeulen, Marc Chadeau-Hyam, Fernando Guntoro, Hugh Montgomery, Meher Preethi Boorgula, Varsha Sreeka, Andrew Goodspeed, Bennett Davenport, Felipe V Pereira, Vadym Zaberezhnyy, Wolfgang E Schleicher, Dexiang Gao, Andreia N Cadar, Michael Papanicolaou, Afshin Beheshti, Stephen B Baylin, James Costello, Jenna M Bartley, Thomas E Morrison, Julio A Aguirre-Ghiso, Mercedes Rincon, James DeGregori
Breast cancer is the second most common cancer globally. Most deaths from breast cancer are due to metastatic disease which often follows long periods of clinical dormancy 1 . Understanding the mechanisms that disrupt the quiescence of dormant disseminated cancer cells (DCC) is crucial for addressing metastatic progression. Infection with respiratory viruses (e.g. influenza or SARS-CoV-2) is common and triggers an inflammatory response locally and systemically 2,3 . Here we show that influenza virus infection leads to loss of the pro-dormancy mesenchymal phenotype in breast DCC in the lung, causing DCC proliferation within days of infection, and a greater than 100-fold expansion of carcinoma cells into metastatic lesions within two weeks...
April 5, 2024: Research Square
#2
JOURNAL ARTICLE
Alison A Chomiak, Rochelle L Tiedemann, Yanqing Liu, Xiangqian Kong, Ying Cui, Ashley K Wiseman, Kate E Thurlow, Evan M Cornett, Michael J Topper, Stephen B Baylin, Scott B Rothbart
DNA methyltransferase inhibitor (DNMTi) efficacy in solid tumors is limited. Colon cancer cells exposed to DNMTi accumulate lysine-27 trimethylation on histone H3 (H3K27me3). We propose this Enhancer of Zeste Homolog 2 (EZH2)-dependent repressive modification limits DNMTi efficacy. Here, we show that low-dose DNMTi treatment sensitizes colon cancer cells to select EZH2 inhibitors (EZH2is). Integrative epigenomic analysis reveals that DNMTi-induced H3K27me3 accumulates at genomic regions poised with EZH2. Notably, combined EZH2i and DNMTi alters the epigenomic landscape to transcriptionally up-regulate the calcium-induced nuclear factor of activated T cells (NFAT):activating protein 1 (AP-1) signaling pathway...
March 29, 2024: Science Advances
#3
Rochelle L Tiedemann, Joel Hrit, Qian Du, Ashley K Wiseman, Hope E Eden, Bradley M Dickson, Xiangqian Kong, Alison A Chomiak, Robert M Vaughan, Jakob M Hebert, Yael David, Wanding Zhou, Stephen B Baylin, Peter A Jones, Susan J Clark, Scott B Rothbart
The RING E3 ubiquitin ligase UHRF1 is an established cofactor for DNA methylation inheritance. Nucleosomal engagement through histone and DNA interactions directs UHRF1 ubiquitin ligase activity toward lysines on histone H3 tails, creating binding sites for DNMT1 through ubiquitin interacting motifs (UIM1 and UIM2). Here, we profile contributions of UHRF1 and DNMT1 to genome-wide DNA methylation inheritance and dissect specific roles for ubiquitin signaling in this process. We reveal DNA methylation maintenance at low-density CpGs is vulnerable to disruption of UHRF1 ubiquitin ligase activity and DNMT1 ubiquitin reading activity through UIM1...
February 16, 2024: bioRxiv
#4
JOURNAL ARTICLE
Lijing Yang, Lei Tu, Shilpa Bisht, Yiqing Mao, Daniel Petkovich, Sara-Jayne Thursby, Jinxiao Liang, Nibedita Patel, Ray-Whay Chiu Yen, Tina Largent, Cynthia Zahnow, Malcolm Brock, Kathy Gabrielson, Kevan J Salimian, Stephen B Baylin, Hariharan Easwaran
Cancers of the same tissue-type but in anatomically distinct locations exhibit different molecular dependencies for tumorigenesis. Proximal and distal colon cancers exemplify such characteristics, with BRAFV600E predominantly occurring in proximal colon cancers along with increased DNA methylation phenotype. Using mouse colon organoids, here we show that proximal and distal colon stem cells have distinct transcriptional programs that regulate stemness and differentiation. We identify that the homeobox transcription factor, CDX2, which is silenced by DNA methylation in proximal colon cancers, is a key mediator of the differential transcriptional programs...
February 15, 2024: Nature Communications
#5
JOURNAL ARTICLE
Valerie Lee, Rose Parkinson, Marianna Zahurak, Leslie Cope, Andrea Cercek, Henk Verheul, Elske Gootjes, Heinz Josef Lenz, Syma Iqbal, Peter Jones, Stephen Baylin, Vandna Rami, Nita Ahuja, Anthony El Khoueiry, Nilofer S Azad
DNA methyltransferase inhibitors (DNMTi) have demonstrated benefit in reversing resistance to systemic therapies for several cancer types. In a phase II trial of guadecitabine and irinotecan compared to regorafenib or TAS-102 in pts with advanced mCRC refractory to irinotecan. Patients with mCRC refractory to irinotecan were randomized 2:1 to guadecitabine and irinotecan (Arm A) vs standard of care regorafenib or TAS-102 (Arm B) on a 28-day cycle. Between January 15, 2016 and October 24, 2018, 104 pts were randomized at four international sites, with 96 pts undergoing treatment, 62 in Arm A and 34 in Arm B...
February 5, 2024: International Journal of Cancer. Journal International du Cancer
#6
Jeffrey Haltom, Nidia S Trovao, Joseph Guarnieri, Pan Vincent, Urminder Singh, Sergey Tsoy, Collin A O'Leary, Yaron Bram, Gabrielle A Widjaja, Zimu Cen, Robert Meller, Stephen B Baylin, Walter N Moss, Basil J Nikolau, Francisco J Enguita, Douglas C Wallace, Afshin Beheshti, Robert Schwartz, Eve Syrkin Wurtele
The orphan gene of SARS-CoV-2, ORF10, is the least studied gene in the virus responsible for the COVID-19 pandemic. Recent experimentation indicated ORF10 expression moderates innate immunity in vitro. However, whether ORF10 affects COVID-19 in humans remained unknown. We determine that the ORF10 sequence is identical to the Wuhan-Hu-1 ancestral haplotype in 95% of genomes across five variants of concern (VOC). Four ORF10 variants are associated with less virulent clinical outcomes in the human host: three of these affect ORF10 protein structure, one affects ORF10 RNA structural dynamics...
November 27, 2023: medRxiv
#7
JOURNAL ARTICLE
Joseph W Guarnieri, Joseph M Dybas, Hossein Fazelinia, Man S Kim, Justin Frere, Yuanchao Zhang, Yentli Soto Albrecht, Deborah G Murdock, Alessia Angelin, Larry N Singh, Scott L Weiss, Sonja M Best, Marie T Lott, Shiping Zhang, Henry Cope, Victoria Zaksas, Amanda Saravia-Butler, Cem Meydan, Jonathan Foox, Christopher Mozsary, Yaron Bram, Yared Kidane, Waldemar Priebe, Mark R Emmett, Robert Meller, Sam Demharter, Valdemar Stentoft-Hansen, Marco Salvatore, Diego Galeano, Francisco J Enguita, Peter Grabham, Nidia S Trovao, Urminder Singh, Jeffrey Haltom, Mark T Heise, Nathaniel J Moorman, Victoria K Baxter, Emily A Madden, Sharon A Taft-Benz, Elizabeth J Anderson, Wes A Sanders, Rebekah J Dickmander, Stephen B Baylin, Eve Syrkin Wurtele, Pedro M Moraes-Vieira, Deanne Taylor, Christopher E Mason, Jonathan C Schisler, Robert E Schwartz, Afshin Beheshti, Douglas C Wallace
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral proteins bind to host mitochondrial proteins, likely inhibiting oxidative phosphorylation (OXPHOS) and stimulating glycolysis. We analyzed mitochondrial gene expression in nasopharyngeal and autopsy tissues from patients with coronavirus disease 2019 (COVID-19). In nasopharyngeal samples with declining viral titers, the virus blocked the transcription of a subset of nuclear DNA (nDNA)-encoded mitochondrial OXPHOS genes, induced the expression of microRNA 2392, activated HIF-1α to induce glycolysis, and activated host immune defenses including the integrated stress response...
August 9, 2023: Science Translational Medicine
#8
JOURNAL ARTICLE
Yuba R Bhandari, Vinod Krishna, Rachael Powers, Sehej Parmar, Sara-Jayne Thursby, Ekta Gupta, Ozlem Kulak, Prashanth Gokare, Joke Reumers, Liesbeth Van Wesenbeeck, Kurtis E Bachman, Stephen B Baylin, Hariharan Easwaran
Colorectal cancers (CRCs) form a heterogenous group classified into epigenetic and transcriptional subtypes. The basis for the epigenetic subtypes, exemplified by varying degrees of promoter DNA hypermethylation, and its relation to the transcriptional subtypes is not well understood. We link cancer-specific transcription factor (TF) expression alterations to methylation alterations near TF-binding sites at promoter and enhancer regions in CRCs and their premalignant precursor lesions to provide mechanistic insights into the origins and evolution of the CRC molecular subtypes...
August 2023: Proceedings of the National Academy of Sciences of the United States of America
#9
JOURNAL ARTICLE
Michael J Topper, Valsamo Anagnostou, Kristen A Marrone, Victor E Velculescu, Peter A Jones, Julie R Brahmer, Stephen B Baylin, Galen H Hostetter
Non-small-cell lung cancer remains a deadly form of human cancer even in the era of immunotherapy with existing immunotherapy strategies currently only benefiting a minority of patients. Therefore, the derivation of treatment options, which might extend the promise of immunotherapy to more patients, remains of paramount importance. Here, we define using TCGA lung squamous and lung adenocarcinoma RNAseq datasets a significant correlation between epigenetic therapy actionable interferon genes with both predicted tumor immune score generally, and CD8A specifically...
July 21, 2023: IScience
#10
JOURNAL ARTICLE
Tomas Kanholm, Uzma Rentia, Melissa Hadley, Jennifer A Karlow, Olivia L Cox, Noor Diab, Matthew L Bendall, Tyson Dawson, James I McDonald, Wenbing Xie, Keith A Crandall, Kathleen H Burns, Stephen B Baylin, Hariharan Easwaran, Katherine B Chiappinelli
Transposable elements (TEs) are typically silenced by DNA methylation and repressive histone modifications in differentiated healthy human tissues. However, TE expression increases in a wide range of cancers and is correlated with global hypomethylation of cancer genomes. We assessed expression and DNA methylation of TEs in fibroblast cells that were serially transduced with hTERT, SV40, and HRASR24C to immortalize and then transform them, which models the different steps of the tumorigenesis process. RNA-sequencing and whole-genome bisulfite sequencing were performed at each stage of transformation...
May 30, 2023: Cancer Research
#11
JOURNAL ARTICLE
Stephen Baylin
No abstract text is available yet for this article.
April 26, 2023: Epigenomics
#12
JOURNAL ARTICLE
H Josh Jang, Galen Hostetter, Alexander W MacFarlane, Zachary Madaj, Eric A Ross, Toshinori Hinoue, Justin R Kulchycki, Ryan S Burgos, Mahvish Tafseer, R Katherine Alpaugh, Candice L Schwebel, Rutika Kokate, Daniel M Geynisman, Matthew R Zibelman, Pooja Ghatalia, Peter W Nichols, Woonbok Chung, Jozef Madzo, Noah M Hahn, David I Quinn, Jean-Pierre J Issa, Michael J Topper, Stephen B Baylin, Hui Shen, Kerry S Campbell, Peter A Jones, Elizabeth R Plimack
PURPOSE: Based on preclinical evidence of epigenetic contribution to sensitivity and resistance to immune checkpoint inhibitors (ICI), we hypothesized that guadecitabine (hypomethylating agent) and atezolizumab (anti-PD-L1) together would potentiate a clinical response in patients with metastatic urothelial carcinoma (UC) unresponsive to initial immune checkpoint blockade therapy. PATIENTS AND METHODS: We designed a single arm Phase II study (NCT03179943) with a safety run-in to identify the recommended phase II dose of the combination therapy of guadecitabine and atezolizumab...
March 16, 2023: Clinical Cancer Research
#13
MULTICENTER STUDY
Casey L O'Connell, Maria R Baer, Andreas Due Ørskov, Sunil Kumar Saini, Vu H Duong, Patricia Kropf, Jakob Werner Hansen, Denice Tsao-Wei, Hyo Sik Jang, Ashkan Emadi, Staffan Holmberg-Thyden, Jack Cowland, Brett T Brinker, Kristin Horwood, Ryan Burgos, Galen Hostetter, Benjamin A Youngblood, Sine Reker Hadrup, Jean-Pierre Issa, Peter Jones, Stephen B Baylin, Imran Siddiqi, Kirsten Grønbaek
PURPOSE: We hypothesized that resistance to hypomethylating agents (HMA) among patients with myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML) would be overcome by combining a programmed death-ligand 1 antibody with an HMA. PATIENTS AND METHODS: We conducted a Phase I/II, multicenter clinical trial for patients with MDS not achieving an International Working Group response after at least 4 cycles of an HMA ("refractory") or progressing after a response ("relapsed") with 3+ or higher risk MDS by the revised International Prognostic Scoring System (IPSS-R) and CMML-1 or -2...
December 15, 2022: Clinical Cancer Research
#14
JOURNAL ARTICLE
Somnath Pandey, Rahinatou Djibo, Anaïs Darracq, Gennaro Calendo, Hanghang Zhang, Ryan A Henry, Andrew J Andrews, Stephen B Baylin, Jozef Madzo, Rafael Najmanovich, Jean-Pierre J Issa, Noël J-M Raynal
Aberrant transcription in cancer cells involves the silencing of tumor suppressor genes (TSGs) and activation of oncogenes. Transcriptomic changes are associated with epigenomic alterations such as DNA-hypermethylation, histone deacetylation, and chromatin condensation in promoter regions of silenced TSGs. To discover novel drugs that trigger TSG reactivation in cancer cells, we used a GFP-reporter system whose expression is silenced by promoter DNA hypermethylation and histone deacetylation. After screening a natural product drug library, we identified that toyocamycin, an adenosine-analog, induces potent GFP reactivation and loss of clonogenicity in human colon cancer cells...
July 8, 2022: Cancers
#15
JOURNAL ARTICLE
Katherine B Chiappinelli, Stephen B Baylin
Cancer cells resist the immune response in a process known as immune editing or immune evasion. Therapies that target the immune system have revolutionized cancer treatment; however, immunotherapies have been ineffective for the majority of ovarian cancer cases. In this issue of the JCI, Chen, Xie, et al. hypothesized that hypomethylating agent (HMA) treatment would induce antitumor immunity to sensitize patients with ovarian cancer to anti-PD-1 immunotherapy. The authors performed a phase II clinical trial to test the combination of guadecitabine, a second-generation HMA, along with pembrolizumab, an immune checkpoint inhibitor of PD-1...
July 15, 2022: Journal of Clinical Investigation
#16
JOURNAL ARTICLE
Aksinija A Kogan, Michael J Topper, Anna J Dellomo, Lora Stojanovic, Lena J McLaughlin, T Michael Creed, Christian L Eberly, Tami J Kingsbury, Maria R Baer, Michael D Kessler, Stephen B Baylin, Feyruz V Rassool
DNA methyltransferase inhibitors (DNMTis) reexpress hypermethylated genes in cancers and leukemias and also activate endogenous retroviruses (ERVs), leading to interferon (IFN) signaling, in a process known as viral mimicry. In the present study we show that in the subset of acute myeloid leukemias (AMLs) with mutations in TP53 , associated with poor prognosis, DNMTis, important drugs for treatment of AML, enable expression of ERVs and IFN and inflammasome signaling in a STING-dependent manner. We previously reported that in solid tumors poly ADP ribose polymerase inhibitors (PARPis) combined with DNMTis to induce an IFN/inflammasome response that is dependent on STING1 and is mechanistically linked to generation of a homologous recombination defect (HRD)...
July 5, 2022: Proceedings of the National Academy of Sciences of the United States of America
#17
JOURNAL ARTICLE
Francisco J Enguita, Ana Lúcia Leitão, J Tyson McDonald, Viktorija Zaksas, Saswati Das, Diego Galeano, Deanne Taylor, Eve Syrkin Wurtele, Amanda Saravia-Butler, Stephen B Baylin, Robert Meller, D Marshall Porterfield, Douglas C Wallace, Jonathan C Schisler, Christopher E Mason, Afshin Beheshti
Rationale: Viral infections are complex processes based on an intricate network of molecular interactions. The infectious agent hijacks components of the cellular machinery for its profit, circumventing the natural defense mechanisms triggered by the infected cell. The successful completion of the replicative viral cycle within a cell depends on the function of viral components versus the cellular defenses. Non-coding RNAs (ncRNAs) are important cellular modulators, either promoting or preventing the progression of viral infections...
2022: Theranostics
#18
JOURNAL ARTICLE
Maria R Baer, Aksinija A Kogan, Søren M Bentzen, Tian Mi, Rena G Lapidus, Vu H Duong, Ashkan Emadi, Sandrine Niyongere, Casey L O'Connell, Benjamin A Youngblood, Stephen B Baylin, Feyruz V Rassool
PURPOSE: Patients with acute myeloid leukemia (AML) unfit for, or resistant to, intensive chemotherapy are often treated with DNA methyltransferase inhibitors (DNMTi). Novel combinations may increase efficacy. In addition to demethylating CpG island gene promoter regions, DNMTis enhance PARP1 recruitment and tight binding to chromatin, preventing PARP-mediated DNA repair, downregulating homologous recombination (HR) DNA repair, and sensitizing cells to PARP inhibitor (PARPi). We previously demonstrated DNMTi and PARPi combination efficacy in AML in vitro and in vivo...
April 1, 2022: Clinical Cancer Research
#19
JOURNAL ARTICLE
Guy Karlebach, Bruce Aronow, Stephen B Baylin, Daniel Butler, Jonathan Foox, Shawn Levy, Cem Meydan, Christopher Mozsary, Amanda M Saravia-Butler, Deanne M Taylor, Eve Wurtele, Christopher E Mason, Afshin Beheshti, Peter N Robinson
Viruses can subvert a number of cellular processes including splicing in order to block innate antiviral responses, and many viruses interact with cellular splicing machinery. SARS-CoV-2 infection was shown to suppress global mRNA splicing, and at least 10 SARS-CoV-2 proteins bind specifically to one or more human RNAs. Here, we investigate 17 published experimental and clinical datasets related to SARS-CoV-2 infection, datasets from the betacoronaviruses SARS-CoV and MERS, as well as Streptococcus pneumonia, HCV, Zika virus, Dengue virus, influenza H3N2, and RSV...
March 2022: Genomics
#20
JOURNAL ARTICLE
Melissa B Pappalardi, Kathryn Keenan, Mark Cockerill, Wendy A Kellner, Alexandra Stowell, Christian Sherk, Kristen Wong, Sarath Pathuri, Jacques Briand, Michael Steidel, Philip Chapman, Arthur Groy, Ashley K Wiseman, Charles F McHugh, Nino Campobasso, Alan P Graves, Emma Fairweather, Thilo Werner, Ali Raoof, Roger J Butlin, Lourdes Rueda, John R Horton, David T Fosbenner, Cunyu Zhang, Jessica L Handler, Morris Muliaditan, Makda Mebrahtu, Jon-Paul Jaworski, Dean E McNulty, Charlotte Burt, H Christian Eberl, Amy N Taylor, Thau Ho, Susan Merrihew, Shawn W Foley, Anna Rutkowska, Mei Li, Stuart P Romeril, Kristin Goldberg, Xing Zhang, Christopher S Kershaw, Marcus Bantscheff, Anthony J Jurewicz, Elisabeth Minthorn, Paola Grandi, Mehul Patel, Andrew B Benowitz, Helai P Mohammad, Aidan G Gilmartin, Rab K Prinjha, Donald Ogilvie, Christopher Carpenter, Dirk Heerding, Stephen B Baylin, Peter A Jones, Xiaodong Cheng, Bryan W King, Juan I Luengo, Allan M Jordan, Ian Waddell, Ryan G Kruger, Michael T McCabe
DNA methylation, a key epigenetic driver of transcriptional silencing, is universally dysregulated in cancer. Reversal of DNA methylation by hypomethylating agents, such as the cytidine analogs decitabine or azacytidine, has demonstrated clinical benefit in hematologic malignancies. These nucleoside analogs are incorporated into replicating DNA where they inhibit DNA cytosine methyltransferases DNMT1, DNMT3A and DNMT3B through irreversible covalent interactions. These agents induce notable toxicity to normal blood cells thus limiting their clinical doses...
October 2021: Nature Cancer
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