Tumor Cell Biodiversity Drives Microenvironmental Reprogramming in Liver Cancer Publication date: Available online 3 October 2019 Source: Cancer Cell Author(s): Lichun Ma, Maria O. Hernandez, Yongmei Zhao, Monika Mehta, Bao Tran, Michael Kelly, Zachary Rae, Jonathan M. Hernandez, Jeremy L. Davis, Sean P. Martin, David E. Kleiner, Stephen M. Hewitt, Kris Ylaya, Bradford J. Wood, Tim F. Greten, Xin Wei Wang Summary
Cellular diversity in tumors is a key factor for therapeutic failures and lethal outcomes of solid malignancies. Here, we determined the single-cell transcriptomic landscape of liver cancer biospecimens from 19 patients. We found varying degrees of heterogeneity in malignant cells within and between tumors and diverse landscapes of tumor microenvironment (TME). Strikingly, tumors with higher transcriptomic diversity were associated with patient's worse overall survival. We found a link between hypoxia-dependent vascular endothelial growth factor expression in tumor diversity and TME polarization. Moreover, T cells from higher heterogeneous tumors showed lower cytolytic activities. Consistent results were found using bulk genomic and transcriptomic profiles of 765 liver tumors. Our results offer insight into the diverse ecosystem of liver cancer and its impact on patient prognosis.
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Pan-Cancer Landscape and Analysis of ERBB2 Mutations Identifies Poziotinib as a Clinically Active Inhibitor and Enhancer of T-DM1 Activity Publication date: Available online 3 October 2019 Source: Cancer Cell Author(s): Jacqulyne P. Robichaux, Yasir Y. Elamin, R.S.K. Vijayan, Monique B. Nilsson, Lemei Hu, Junqin He, Fahao Zhang, Marlese Pisegna, Alissa Poteete, Huiying Sun, Shuai Li, Ting Chen, Han Han, Marcelo Vailati Negrao, Jordi Rodon Ahnert, Lixia Diao, Jing Wang, Xiuning Le, Funda Meric-Bernstam, Mark Routbort Summary
We characterized the landscape and drug sensitivity of ERBB2 (HER2) mutations in cancers. In 11 datasets (n = 211,726), ERBB2 mutational hotspots varied across 25 tumor types. Common HER2 mutants yielded differential sensitivities to eleven EGFR/HER2 tyrosine kinase inhibitors (TKIs) in vitro, and molecular dynamics simulations revealed that mutants with a reduced drug-binding pocket volume were associated with decreased affinity for larger TKIs. Overall, poziotinib was the most potent HER2 mutant-selective TKI tested. Phase II clinical testing in ERBB2 exon 20-mutant non-small cell lung cancer resulted in a confirmed objective response rate of 42% in the first 12 evaluable patients. In pre-clinical models, poziotinib upregulated HER2 cell-surface expression and potentiated the activity of T-DM1, resulting in complete tumor regression with combination treatment.
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Dynamic Incorporation of Histone H3 Variants into Chromatin Is Essential for Acquisition of Aggressive Traits and Metastatic Colonization Publication date: Available online 26 September 2019 Source: Cancer Cell Author(s): Ana P. Gomes, Didem Ilter, Vivien Low, Adam Rosenzweig, Zih-Jie Shen, Tanya Schild, Martin A. Rivas, Ekrem E. Er, Dylan R. McNally, Anders P. Mutvei, Julie Han, Yi-Hung Ou, Paola Cavaliere, Edouard Mullarky, Michal Nagiec, Sejeong Shin, Sang-Oh Yoon, Noah Dephoure, Joan Massagué, Ari M. Melnick Summary
Metastasis is the leading cause of cancer mortality. Chromatin remodeling provides the foundation for the cellular reprogramming necessary to drive metastasis. However, little is known about the nature of this remodeling and its regulation. Here, we show that metastasis-inducing pathways regulate histone chaperones to reduce canonical histone incorporation into chromatin, triggering deposition of H3.3 variant at the promoters of poor-prognosis genes and metastasis-inducing transcription factors. This specific incorporation of H3.3 into chromatin is both necessary and sufficient for the induction of aggressive traits that allow for metastasis formation. Together, our data clearly show incorporation of histone variant H3.3 into chromatin as a major regulator of cell fate during tumorigenesis, and histone chaperones as valuable therapeutic targets for invasive carcinomas.
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An Evolutionarily Conserved Function of Polycomb Silences the MHC Class I Antigen Presentation Pathway and Enables Immune Evasion in Cancer Publication date: Available online 26 September 2019 Source: Cancer Cell Author(s): Marian L. Burr, Christina E. Sparbier, Kah Lok Chan, Yih-Chih Chan, Ariena Kersbergen, Enid Y.N. Lam, Elizabeth Azidis-Yates, Dane Vassiliadis, Charles C. Bell, Omer Gilan, Susan Jackson, Lavinia Tan, Stephen Q. Wong, Sebastian Hollizeck, Ewa M. Michalak, Hannah V. Siddle, Michael T. McCabe, Rab K. Prinjha, Glen R. Guerra, Benjamin J. Solomon Summary
Loss of MHC class I (MHC-I) antigen presentation in cancer cells can elicit immunotherapy resistance. A genome-wide CRISPR/Cas9 screen identified an evolutionarily conserved function of polycomb repressive complex 2 (PRC2) that mediates coordinated transcriptional silencing of the MHC-I antigen processing pathway (MHC-I APP), promoting evasion of T cell-mediated immunity. MHC-I APP gene promoters in MHC-I low cancers harbor bivalent activating H3K4me3 and repressive H3K27me3 histone modifications, silencing basal MHC-I expression and restricting cytokine-induced upregulation. Bivalent chromatin at MHC-I APP genes is a normal developmental process active in embryonic stem cells and maintained during neural progenitor differentiation. This physiological MHC-I silencing highlights a conserved mechanism by which cancers arising from these primitive tissues exploit PRC2 activity to enable immune evasion.
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Mitochondrial Reprogramming Underlies Resistance to BCL-2 Inhibition in Lymphoid Malignancies Publication date: Available online 19 September 2019 Source: Cancer Cell Author(s): Romain Guièze, Vivian M. Liu, Daniel Rosebrock, Alexis A. Jourdain, María Hernández-Sánchez, Aina Martinez Zurita, Jing Sun, Elisa Ten Hacken, Kaitlyn Baranowski, Philip A. Thompson, Jin-Mi Heo, Zachary Cartun, Ozan Aygün, J. Bryan Iorgulescu, Wandi Zhang, Giulia Notarangelo, Dimitri Livitz, Shuqiang Li, Matthew S. Davids, Anat Biran Summary
Mitochondrial apoptosis can be effectively targeted in lymphoid malignancies with the FDA-approved B cell lymphoma 2 (BCL-2) inhibitor venetoclax, but resistance to this agent is emerging. We show that venetoclax resistance in chronic lymphocytic leukemia is associated with complex clonal shifts. To identify determinants of resistance, we conducted parallel genome-scale screens of the BCL-2-driven OCI-Ly1 lymphoma cell line after venetoclax exposure along with integrated expression profiling and functional characterization of drug-resistant and engineered cell lines. We identified regulators of lymphoid transcription and cellular energy metabolism as drivers of venetoclax resistance in addition to the known involvement by BCL-2 family members, which were confirmed in patient samples. Our data support the implementation of combinatorial therapy with metabolic modulators to address venetoclax resistance.
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Combining the Allosteric Inhibitor Asciminib with Ponatinib Suppresses Emergence of and Restores Efficacy against Highly Resistant BCR-ABL1 Mutants Publication date: Available online 19 September 2019 Source: Cancer Cell Author(s): Christopher A. Eide, Matthew S. Zabriskie, Samantha L. Savage Stevens, Orlando Antelope, Nadeem A. Vellore, Hein Than, Anna Reister Schultz, Phillip Clair, Amber D. Bowler, Anthony D. Pomicter, Dongqing Yan, Anna V. Senina, Wang Qiang, Todd W. Kelley, Philippe Szankasi, Michael C. Heinrich, Jeffrey W. Tyner, Delphine Rea, Jean-Michel Cayuela, Dong-Wook Kim Summary
BCR-ABL1 point mutation-mediated resistance to tyrosine kinase inhibitor (TKI) therapy in Philadelphia chromosome-positive (Ph+) leukemia is effectively managed with several approved drugs, including ponatinib for BCR-ABL1T315I-mutant disease. However, therapy options are limited for patients with leukemic clones bearing multiple BCR-ABL1 mutations. Asciminib, an allosteric inhibitor targeting the myristoyl-binding pocket of BCR-ABL1, is active against most single mutants but ineffective against all tested compound mutants. We demonstrate that combining asciminib with ATP site TKIs enhances target inhibition and suppression of resistant outgrowth in Ph+ clinical isolates and cell lines. Inclusion of asciminib restores ponatinib's effectiveness against currently untreatable compound mutants at clinically achievable concentrations. Our findings support combining asciminib with ponatinib as a treatment strategy for this molecularly defined group of patients.
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GAPDH Overexpression in the T Cell Lineage Promotes Angioimmunoblastic T Cell Lymphoma through an NF-κB-Dependent Mechanism Publication date: 16 September 2019 Source: Cancer Cell, Volume 36, Issue 3 Author(s): Laura Mondragón, Rana Mhaidly, Gian Marco De Donatis, Marie Tosolini, Pascal Dao, Anthony R. Martin, Caroline Pons, Johanna Chiche, Marie Jacquin, Véronique Imbert, Emma Proïcs, Laurent Boyer, Anne Doye, Frédéric Luciano, Jaap G. Neels, Frédéric Coutant, Nicole Fabien, Laura Sormani, Camila Rubio-Patiño, Jozef P. Bossowski Summary
GAPDH is emerging as a key player in T cell development and function. To investigate the role of GAPDH in T cells, we generated a transgenic mouse model overexpressing GAPDH in the T cell lineage. Aged mice developed a peripheral Tfh-like lymphoma that recapitulated key molecular, pathological, and immunophenotypic features of human angioimmunoblastic T cell lymphoma (AITL). GAPDH induced non-canonical NF-κB pathway activation in mouse T cells, which was strongly activated in human AITL. We developed a NIK inhibitor to reveal that targeting the NF-κB pathway prolonged AITL-bearing mouse survival alone and in combination with anti-PD-1. These findings suggest the therapeutic potential of targeting NF-κB signaling in AITL and provide a model for future AITL therapeutic investigations.
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Age-Related Gliosis Promotes Central Nervous System Lymphoma through CCL19-Mediated Tumor Cell Retention Publication date: 16 September 2019 Source: Cancer Cell, Volume 36, Issue 3 Author(s): Tracy O'Connor, Xiaolan Zhou, Jan Kosla, Arlind Adili, Maria Garcia Beccaria, Elena Kotsiliti, Dominik Pfister, Anna-Lena Johlke, Ankit Sinha, Roman Sankowski, Markus Schick, Richard Lewis, Nikolaos Dokalis, Bastian Seubert, Bastian Höchst, Donato Inverso, Danijela Heide, Wenlong Zhang, Petra Weihrich, Katrin Manske Summary
How lymphoma cells (LCs) invade the brain during the development of central nervous system lymphoma (CNSL) is unclear. We found that NF-κB-induced gliosis promotes CNSL in immunocompetent mice. Gliosis elevated cell-adhesion molecules, which increased LCs in the brain but was insufficient to induce CNSL. Astrocyte-derived CCL19 was required for gliosis-induced CNSL. Deleting CCL19 in mice or CCR7 from LCs abrogated CNSL development. Two-photon microscopy revealed LCs transiently entering normal brain parenchyma. Astrocytic CCL19 enhanced parenchymal CNS retention of LCs, thereby promoting CNSL formation. Aged, gliotic wild-type mice were more susceptible to forming CNSL than young wild-type mice, and astrocytic CCL19 was observed in both human gliosis and CNSL. Therefore, CCL19-CCR7 interactions may underlie an increased age-related risk for CNSL.
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LMO2 Confers Synthetic Lethality to PARP Inhibition in DLBCL Publication date: 16 September 2019 Source: Cancer Cell, Volume 36, Issue 3 Author(s): Salma Parvin, Ariel Ramirez-Labrada, Shlomzion Aumann, XiaoQing Lu, Natalia Weich, Gabriel Santiago, Elena M. Cortizas, Eden Sharabi, Yu Zhang, Isidro Sanchez-Garcia, Andrew J. Gentles, Evan Roberts, Daniel Bilbao-Cortes, Francisco Vega, Jennifer R. Chapman, Ramiro E. Verdun, Izidore S. Lossos Summary
Deficiency in DNA double-strand break (DSB) repair mechanisms has been widely exploited for the treatment of different malignances, including homologous recombination (HR)-deficient breast and ovarian cancers. Here we demonstrate that diffuse large B cell lymphomas (DLBCLs) expressing LMO2 protein are functionally deficient in HR-mediated DSB repair. Mechanistically, LMO2 inhibits BRCA1 recruitment to DSBs by interacting with 53BP1 during repair. Similar to BRCA1-deficient cells, LMO2-positive DLBCLs and T cell acute lymphoblastic leukemia (T-ALL) cells exhibit a high sensitivity to poly(ADP-ribose) polymerase (PARP) inhibitors. Furthermore, chemotherapy and PARP inhibitors synergize to inhibit the growth of LMO2-positive tumors. Together, our results reveal that LMO2 expression predicts HR deficiency and the potential therapeutic use of PARP inhibitors in DLBCL and T-ALL.
Graphical Abstract |
The Dual Roles of the Atypical Protein Kinase Cs in Cancer Publication date: 16 September 2019 Source: Cancer Cell, Volume 36, Issue 3 Author(s): Miguel Reina-Campos, Maria T. Diaz-Meco, Jorge Moscat
Atypical protein kinase C (aPKC) isozymes, PKCλ/ι and PKCζ, are now considered fundamental regulators of tumorigenesis. However, the specific separation of functions that determine their different roles in cancer is still being unraveled. Both aPKCs have pleiotropic context-dependent functions that can translate into tumor-promoter or -suppressive functions. Here, we review early and more recent literature to discuss how the different tumor types, and their microenvironments, might account for the selective signaling of each aPKC isotype. This is of clinical relevance because a better understanding of the roles of these kinases is essential for the design of new anti-cancer treatments.
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Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00302841026182,00306932607174,alsfakia@gmail.com,
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00306932607174,
alsfakia@gmail.com,
Anapafseos 5 Agios Nikolaos 72100 Crete Greece,
Medicine by Alexandros G. Sfakianakis,
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