| Genomic and Transcriptomic Profiling of Combined Hepatocellular and Intrahepatic Cholangiocarcinoma Reveals Distinct Molecular Subtypes Publication date: Available online 23 May 2019 Source: Cancer Cell Author(s): Ruidong Xue, Lu Chen, Chong Zhang, Masashi Fujita, Ruoyan Li, Shu-Mei Yan, Choon Kiat Ong, Xiwen Liao, Qiang Gao, Shota Sasagawa, Yanmeng Li, Jincheng Wang, Hua Guo, Qi-Tao Huang, Qian Zhong, Jing Tan, Lisha Qi, Wenchen Gong, Zhixian Hong, Meng Li SummaryWe performed genomic and transcriptomic sequencing of 133 combined hepatocellular and intrahepatic cholangiocarcinoma (cHCC-ICC) cases, including separate, combined, and mixed subtypes. Integrative comparison of cHCC-ICC with hepatocellular carcinoma and intrahepatic cholangiocarcinoma revealed that combined and mixed type cHCC-ICCs are distinct subtypes with different clinical and molecular features. Integrating laser microdissection, cancer cell fraction analysis, and single nucleus sequencing, we revealed both mono- and multiclonal origins in the separate type cHCC-ICCs, whereas combined and mixed type cHCC-ICCs were all monoclonal origin. Notably, cHCC-ICCs showed significantly higher expression of Nestin, suggesting Nestin may serve as a biomarker for diagnosing cHCC-ICC. Our results provide important biological and clinical insights into cHCC-ICC. Graphical Abstract |
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Publication date: Available online 16 May 2019
Source: Cancer Cell
Author(s): Behrouz Hassannia, Peter Vandenabeele, Tom Vanden Berghe
One of the key challenges in cancer research is how to effectively kill cancer cells while leaving the healthy cells intact. Cancer cells often have defects in cell death executioner mechanisms, which is one of the main reasons for therapy resistance. To enable growth, cancer cells exhibit an increased iron demand compared with normal, non-cancer cells. This iron dependency can make cancer cells more vulnerable to iron-catalyzed necrosis, referred to as ferroptosis. The identification of FDA-approved drugs as ferroptosis inducers creates high expectations for the potential of ferroptosis to be a new promising way to kill therapy-resistant cancers.
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Publication date: 13 May 2019
Source: Cancer Cell, Volume 35, Issue 5
Author(s): Mohamed Elgendy, Marco Cirò, Amir Hosseini, Jakob Weiszmann, Luca Mazzarella, Elisa Ferrari, Riccardo Cazzoli, Giuseppe Curigliano, Andrea DeCensi, Bernardo Bonanni, Alfredo Budillon, Pier Giuseppe Pelicci, Veerle Janssens, Manfred Ogris, Manuela Baccarini, Luisa Lanfrancone, Wolfram Weckwerth, Marco Foiani, Saverio Minucci
Summary
Tumor cells may adapt to metabolic challenges by alternating between glycolysis and oxidative phosphorylation (OXPHOS). To target this metabolic plasticity, we combined intermittent fasting, a clinically feasible approach to reduce glucose availability, with the OXPHOS inhibitor metformin. In mice exposed to 24-h feeding/fasting cycles, metformin impaired tumor growth only when administered during fasting-induced hypoglycemia. Synergistic anti-neoplastic effects of the metformin/hypoglycemia combination were mediated by glycogen synthase kinase 3β (GSK3β) activation downstream of PP2A, leading to a decline in the pro-survival protein MCL-1, and cell death. Mechanistically, specific activation of the PP2A-GSK3β axis was the sum of metformin-induced inhibition of CIP2A, a PP2A suppressor, and of upregulation of the PP2A regulatory subunit B56δ by low glucose, leading to an active PP2A-B56δ complex with high affinity toward GSK3β.
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Publication date: 13 May 2019
Source: Cancer Cell, Volume 35, Issue 5
Author(s): Brian Krug, Nicolas De Jay, Ashot S. Harutyunyan, Shriya Deshmukh, Dylan M. Marchione, Paul Guilhamon, Kelsey C. Bertrand, Leonie G. Mikael, Melissa K. McConechy, Carol C.L. Chen, Sima Khazaei, Robert F. Koncar, Sameer Agnihotri, Damien Faury, Benjamin Ellezam, Alexander G. Weil, Josie Ursini-Siegel, Daniel D. De Carvalho, Peter B. Dirks, Peter W. Lewis
Summary
High-grade gliomas defined by histone 3 K27M driver mutations exhibit global loss of H3K27 trimethylation and reciprocal gain of H3K27 acetylation, respectively shaping repressive and active chromatin landscapes. We generated tumor-derived isogenic models bearing this mutation and show that it leads to pervasive H3K27ac deposition across the genome. In turn, active enhancers and promoters are not created de novo and instead reflect the epigenomic landscape of the cell of origin. H3K27ac is enriched at repeat elements, resulting in their increased expression, which in turn can be further amplified by DNA demethylation and histone deacetylase inhibitors providing an exquisite therapeutic vulnerability. These agents may therefore modulate anti-tumor immune responses as a therapeutic modality for this untreatable disease.
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Publication date: 13 May 2019
Source: Cancer Cell, Volume 35, Issue 5
Author(s): Mercedes Segovia, Sofia Russo, Mathias Jeldres, Yamil D. Mahmoud, Valentina Perez, Maite Duhalde, Pierre Charnet, Matthieu Rousset, Sabina Victoria, Florencia Veigas, Cédric Louvet, Bernard Vanhove, R. Andrés Floto, Ignacio Anegon, Maria Cristina Cuturi, M. Romina Girotti, Gabriel A. Rabinovich, Marcelo Hill
Summary
Although immune checkpoint blockers have yielded significant clinical benefits in patients with different malignancies, the efficacy of these therapies is still limited. Here, we show that disruption of transmembrane protein 176B (TMEM176B) contributes to CD8+ T cell-mediated tumor growth inhibition by unleashing inflammasome activation. Lack of Tmem176b enhances the antitumor activity of anti-CTLA-4 antibodies through mechanisms involving caspase-1/IL-1β activation. Accordingly, patients responding to checkpoint blockade therapies display an activated inflammasome signature. Finally, we identify BayK8644 as a potent TMEM176B inhibitor that promotes CD8+ T cell-mediated tumor control and reinforces the antitumor activity of both anti-CTLA-4 and anti-PD-1 antibodies. Thus, pharmacologic de-repression of the inflammasome by targeting TMEM176B may enhance the therapeutic efficacy of immune checkpoint blockers.
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Publication date: 13 May 2019
Source: Cancer Cell, Volume 35, Issue 5
Author(s): Xiaohong Zhao, Yuan Ren, Matthew Lawlor, Bijal D. Shah, Paul M.C. Park, Tint Lwin, Xuefeng Wang, Kenian Liu, Michelle Wang, Jing Gao, Tao Li, Mousheng Xu, Ariosto S. Silva, Kaplan Lee, Tinghu Zhang, John M. Koomen, Huijuan Jiang, Praneeth R. Sudalagunta, Mark B. Meads, Fengdong Cheng
Summary
Drug-tolerant "persister" tumor cells underlie emergence of drug-resistant clones and contribute to relapse and disease progression. Here we report that resistance to the BCL-2 targeting drug ABT-199 in models of mantle cell lymphoma and double-hit lymphoma evolves from outgrowth of persister clones displaying loss of 18q21 amplicons that harbor BCL2. Further, persister status is generated via adaptive super-enhancer remodeling that reprograms transcription and offers opportunities for overcoming ABT-199 resistance. Notably, pharmacoproteomic and pharmacogenomic screens revealed that persisters are vulnerable to inhibition of the transcriptional machinery and especially to inhibition of cyclin-dependent kinase 7 (CDK7), which is essential for the transcriptional reprogramming that drives and sustains ABT-199 resistance. Thus, transcription-targeting agents offer new approaches to disable drug resistance in B-cell lymphomas.
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Publication date: 13 May 2019
Source: Cancer Cell, Volume 35, Issue 5
Author(s): Bryan D. Smith, Michael D. Kaufman, Wei-Ping Lu, Anu Gupta, Cynthia B. Leary, Scott C. Wise, Thomas J. Rutkoski, Yu Mi Ahn, Gada Al-Ani, Stacie L. Bulfer, Timothy M. Caldwell, Lawrence Chun, Carol L. Ensinger, Molly M. Hood, Arin McKinley, William C. Patt, Rodrigo Ruiz-Soto, Ying Su, Hanumaiah Telikepalli, Ajia Town
Summary
Ripretinib (DCC-2618) was designed to inhibit the full spectrum of mutant KIT and PDGFRA kinases found in cancers and myeloproliferative neoplasms, particularly in gastrointestinal stromal tumors (GISTs), in which the heterogeneity of drug-resistant KIT mutations is a major challenge. Ripretinib is a "switch-control" kinase inhibitor that forces the activation loop (or activation "switch") into an inactive conformation. Ripretinib inhibits all tested KIT and PDGFRA mutants, and notably is a type II kinase inhibitor demonstrated to broadly inhibit activation loop mutations in KIT and PDGFRA, previously thought only achievable with type I inhibitors. Ripretinib shows efficacy in preclinical cancer models, and preliminary clinical data provide proof-of-concept that ripretinib inhibits a wide range of KIT mutants in patients with drug-resistant GISTs.
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Publication date: 13 May 2019
Source: Cancer Cell, Volume 35, Issue 5
Author(s): Jo Ishizawa, Sarah F. Zarabi, R. Eric Davis, Ondrej Halgas, Takenobu Nii, Yulia Jitkova, Ran Zhao, Jonathan St-Germain, Lauren E. Heese, Grace Egan, Vivian R. Ruvolo, Samir H. Barghout, Yuki Nishida, Rose Hurren, Wencai Ma, Marcela Gronda, Todd Link, Keith Wong, Mark Mabanglo, Kensuke Kojima
Summary
The mitochondrial caseinolytic protease P (ClpP) plays a central role in mitochondrial protein quality control by degrading misfolded proteins. Using genetic and chemical approaches, we showed that hyperactivation of the protease selectively kills cancer cells, independently of p53 status, by selective degradation of its respiratory chain protein substrates and disrupts mitochondrial structure and function, while it does not affect non-malignant cells. We identified imipridones as potent activators of ClpP. Through biochemical studies and crystallography, we show that imipridones bind ClpP non-covalently and induce proteolysis by diverse structural changes. Imipridones are presently in clinical trials. Our findings suggest a general concept of inducing cancer cell lethality through activation of mitochondrial proteolysis.
The Fire within: Cell-Autonomous Mechanisms in Inflammation-Driven Cancer
Publication date: 13 May 2019
Source: Cancer Cell, Volume 35, Issue 5
Author(s): Jelena Todoric, Michael Karin
Inflammatory cells are important for tumor initiation and promotion, providing cancer cells with cytokines that enhance cell proliferation and survival. Although malignant epithelial cells were traditionally considered to be on the receiving end of these microenvironmental interactions, recent studies show that epithelial cells can undergo inflammatory reprogramming on their own. Such epigenetic switches are often triggered by chronic tissue injury and play important roles in tissue repair. By converting terminally differentiated cells that harbor even a single oncogenic mutation to a less differentiated state with a higher proliferative potential, cell-autonomous inflammation is an important contributor to tumor initiation.
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Publication date: 13 May 2019
Source: Cancer Cell, Volume 35, Issue 5
Author(s): Luc G.T. Morris, Timothy A. Chan
During the development and progression of tumors, cancer cells undergo clonal selection due to a variety of genetic and microenvironmental factors. A recent report presents insights demonstrating the interplay between neoantigens and the immune system in untreated non-small-cell lung cancers.
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