Cancer Cell

RAC1P29S Induces a Mesenchymal Phenotypic Switch via Serum Response Factor to Promote Melanoma Development and Therapy Resistance Publication date: Available online 27 June 2019 Source: Cancer Cell Author(s): Daniël A. Lionarons, David C. Hancock, Sareena Rana, Philip East, Christopher Moore, Miguel M. Murillo, Joana Carvalho, Bradley Spencer-Dene, Eleanor Herbert, Gordon Stamp, Djamil Damry, Dinis P. Calado, Ian Rosewell, Ralph Fritsch, Richard R. Neubig, Miriam Molina-Arcas, Julian Downward Summary RAC1 P29 is the third most commonly mutated codon in human cutaneous melanoma, after BRAF V600 and NRAS Q61. Here, we study the role of RAC1P29S in melanoma development and reveal that RAC1P29S activates PAK, AKT, and a gene expression program initiated by the SRF/MRTF transcriptional pathway, which results in a melanocytic to mesenchymal phenotypic switch. Mice with ubiquitous expression of RAC1P29S from the endogenous locus develop lymphoma. When expressed only in melanocytes, RAC1P29S cooperates with oncogenic BRAF or with NF1-loss to promote tumorigenesis. RAC1P29S also drives resistance to BRAF inhibitors, which is reversed by SRF/MRTF inhibitors. These findings establish RAC1P29S as a promoter of melanoma initiation and mediator of therapy resistance, while identifying SRF/MRTF as a potential therapeutic target. Graphical Abstract

Anti-tumor Activity of the Type I PRMT Inhibitor, GSK3368715, Synergizes with PRMT5 Inhibition through MTAP Loss Publication date: Available online 27 June 2019 Source: Cancer Cell Author(s): Andrew Fedoriw, Satyajit R. Rajapurkar, Shane O'Brien, Sarah V. Gerhart, Lorna H. Mitchell, Nicholas D. Adams, Nathalie Rioux, Trupti Lingaraj, Scott A. Ribich, Melissa B. Pappalardi, Niyant Shah, Jenny Laraio, Yan Liu, Michael Butticello, Chris L. Carpenter, Caretha Creasy, Susan Korenchuk, Michael T. McCabe, Charles F. McHugh, Raman Nagarajan Summary Type I protein arginine methyltransferases (PRMTs) catalyze asymmetric dimethylation of arginines on proteins. Type I PRMTs and their substrates have been implicated in human cancers, suggesting inhibition of type I PRMTs may offer a therapeutic approach for oncology. The current report describes GSK3368715 (EPZ019997), a potent, reversible type I PRMT inhibitor with anti-tumor effects in human cancer models. Inhibition of PRMT5, the predominant type II PRMT, produces synergistic cancer cell growth inhibition when combined with GSK3368715. Interestingly, deletion of the methylthioadenosine phosphorylase gene (MTAP) results in accumulation of the metabolite 2-methylthioadenosine, an endogenous inhibitor of PRMT5, and correlates with sensitivity to GSK3368715 in cell lines. These data provide rationale to explore MTAP status as a biomarker strategy for patient selection. Graphical Abstract

A Biparatopic HER2-Targeting Antibody-Drug Conjugate Induces Tumor Regression in Primary Models Refractory to or Ineligible for HER2-Targeted Therapy Publication date: 10 June 2019 Source: Cancer Cell, Volume 35, Issue 6 Author(s): John Y. Li, Samuel R. Perry, Vanessa Muniz-Medina, Xinzhong Wang, Leslie K. Wetzel, Marlon C. Rebelatto, Mary Jane Masson Hinrichs, Binyam Z. Bezabeh, Ryan L. Fleming, Nazzareno Dimasi, Hui Feng, Dorin Toader, Andy Q. Yuan, Lan Xu, Jia Lin, Changshou Gao, Herren Wu, Rakesh Dixit, Jane K. Osbourn, Steven R. Coats

Genomic and Transcriptomic Profiling of Combined Hepatocellular and Intrahepatic Cholangiocarcinoma Reveals Distinct Molecular Subtypes Publication date: 10 June 2019 Source: Cancer Cell, Volume 35, Issue 6 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 Summary We 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

Non-oncogene Addiction to SIRT3 Plays a Critical Role in Lymphomagenesis Publication date: 10 June 2019 Source: Cancer Cell, Volume 35, Issue 6 Author(s): Meng Li, Ying-Ling Chiang, Costas A. Lyssiotis, Matthew R. Teater, Jun Young Hong, Hao Shen, Ling Wang, Jing Hu, Hui Jing, Zhengming Chen, Neeraj Jain, Cihangir Duy, Sucharita J. Mistry, Leandro Cerchietti, Justin R. Cross, Lewis C. Cantley, Michael R. Green, Hening Lin, Ari M. Melnick Summary Diffuse large B cell lymphomas (DLBCLs) are genetically heterogeneous and highly proliferative neoplasms derived from germinal center (GC) B cells. Here, we show that DLBCLs are dependent on mitochondrial lysine deacetylase SIRT3 for proliferation, survival, self-renewal, and tumor growth in vivo regardless of disease subtype and genetics. SIRT3 knockout attenuated B cell lymphomagenesis in VavP-Bcl2 mice without affecting normal GC formation. Mechanistically, SIRT3 depletion impaired glutamine flux to the TCA cycle via glutamate dehydrogenase and reduction in acetyl-CoA pools, which in turn induce autophagy and cell death. We developed a mitochondrial-targeted class I sirtuin inhibitor, YC8-02, which phenocopied the effects of SIRT3 depletion and killed DLBCL cells. SIRT3 is thus a metabolic non-oncogene addiction and therapeutic target for DLBCLs. Graphical Abstract

Targeting Tumors with IL-10 Prevents Dendritic Cell-Mediated CD8+ T Cell Apoptosis Publication date: 10 June 2019 Source: Cancer Cell, Volume 35, Issue 6 Author(s): Jian Qiao, Zhida Liu, Chunbo Dong, Yan Luan, Anli Zhang, Casey Moore, Kai Fu, Jianjian Peng, Yang Wang, Zhenhua Ren, Chuanhui Han, Ting Xu, Yang-Xin Fu Summary Increasing evidence demonstrates that interleukin-10 (IL-10), known as an immunosuppressive cytokine, induces antitumor effects depending on CD8+ T cells. However, it remains elusive how immunosuppressive effects of IL-10 contribute to CD8+ T cell-mediated antitumor immunity. We generated Cetuximab-based IL-10 fusion protein (CmAb-(IL10)2) to prolong its half-life and allow tumor-targeted delivery of IL-10. Our results demonstrated potent antitumor effects of CmAb-(IL10)2 with reduced toxicity. Moreover, we revealed a mechanism of CmAb-(IL10)2 preventing dendritic cell (DC)-mediated CD8+ tumor-infiltrating lymphocyte apoptosis through regulating IFN-γ production. When combined with immune checkpoint blockade, CmAb-(IL10)2 significantly improves antitumor effects in mice with advanced tumors. Our findings reveal a DC-regulating role of IL-10 to potentiate CD8+ T cell-mediated antitumor immunity and provide a potential strategy to improve cancer immunotherapy. Graphical Abstract

Cooperation between Constitutive and Inducible Chemokines Enables T Cell Engraftment and Immune Attack in Solid Tumors Publication date: 10 June 2019 Source: Cancer Cell, Volume 35, Issue 6 Author(s): Denarda Dangaj, Marine Bruand, Alizée J. Grimm, Catherine Ronet, David Barras, Priyanka A. Duttagupta, Evripidis Lanitis, Jaikumar Duraiswamy, Janos L. Tanyi, Fabian Benencia, Jose Conejo-Garcia, Hena R. Ramay, Kathleen T. Montone, Daniel J. Powell, Phyllis A. Gimotty, Andrea Facciabene, Donald G. Jackson, Jeffrey S. Weber, Scott J. Rodig, Stephen F. Hodi Summary We investigated the role of chemokines in regulating T cell accumulation in solid tumors. CCL5 and CXCL9 overexpression was associated with CD8+ T cell infiltration in solid tumors. T cell infiltration required tumor cell-derived CCL5 and was amplified by IFN-γ-inducible, myeloid cell-secreted CXCL9. CCL5 and CXCL9 coexpression revealed immunoreactive tumors with prolonged survival and response to checkpoint blockade. Loss of CCL5 expression in human tumors was associated with epigenetic silencing through DNA methylation. Reduction of CCL5 expression caused tumor-infiltrating lymphocyte (TIL) desertification, whereas forced CCL5 expression prevented Cxcl9 expression and TILs loss, and attenuated tumor growth in mice through IFN-γ. The cooperation between tumor-derived CCL5 and IFN-γ-inducible CXCR3 ligands secreted by myeloid cells is key for orchestrating T cell infiltration in immunoreactive and immunoresponsive tumors. Graphical Abstract

Symbiotic Macrophage-Glioma Cell Interactions Reveal Synthetic Lethality in PTEN-Null Glioma Publication date: 10 June 2019 Source: Cancer Cell, Volume 35, Issue 6 Author(s): Peiwen Chen, Di Zhao, Jun Li, Xin Liang, Jiexi Li, Andrew Chang, Verlene K. Henry, Zhengdao Lan, Denise J. Spring, Ganesh Rao, Y. Alan Wang, Ronald A. DePinho Summary Heterotypic interactions across diverse cell types can enable tumor progression and hold the potential to expand therapeutic interventions. Here, combined profiling and functional studies of glioma cells in glioblastoma multiforme (GBM) models establish that PTEN deficiency activates YAP1, which directly upregulates lysyl oxidase (LOX) expression. Mechanistically, secreted LOX functions as a potent macrophage chemoattractant via activation of the β1 integrin-PYK2 pathway in macrophages. These infiltrating macrophages secrete SPP1, which sustains glioma cell survival and stimulates angiogenesis. In PTEN-null GBM models, LOX inhibition markedly suppresses macrophage infiltration and tumor progression. Correspondingly, YAP1-LOX and β1 integrin-SPP1 signaling correlates positively with higher macrophage density and lower overall survival in GBM patients. This symbiotic glioma-macrophage interplay provides therapeutic targets specifically for PTEN-deficient GBM. Graphical Abstract

Sequential Therapy with PARP and WEE1 Inhibitors Minimizes Toxicity while Maintaining Efficacy Publication date: 10 June 2019 Source: Cancer Cell, Volume 35, Issue 6 Author(s): Yong Fang, Daniel J. McGrail, Chaoyang Sun, Marilyne Labrie, Xiaohua Chen, Dong Zhang, Zhenlin Ju, Christopher P. Vellano, Yiling Lu, Yongsheng Li, Kang Jin Jeong, Zhiyong Ding, Jiyong Liang, Steven W. Wang, Hui Dai, Sanghoon Lee, Nidhi Sahni, Imelda Mercado-Uribe, Tae-beom Kim, Ken Chen Summary We demonstrate that concurrent administration of poly(ADP-ribose) polymerase (PARP) and WEE1 inhibitors is effective in inhibiting tumor growth but poorly tolerated. Concurrent treatment with PARP and WEE1 inhibitors induces replication stress, DNA damage, and abrogates the G2 DNA damage checkpoint in both normal and malignant cells. Following cessation of monotherapy with PARP or WEE1 inhibitors, effects of these inhibitors persist suggesting that sequential administration of PARP and WEE1 inhibitors could maintain efficacy while ameliorating toxicity. Strikingly, while sequential administration mirrored concurrent therapy in cancer cells that have high basal replication stress, low basal replication stress in normal cells protected them from DNA damage and toxicity, thus improving tolerability while preserving efficacy in ovarian cancer xenograft and patient-derived xenograft models. Graphical Abstract

Targeting Ferroptosis to Iron Out Cancer Publication date: 10 June 2019 Source: Cancer Cell, Volume 35, Issue 6 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.