Oncology
Abstract
Mechanisms driving tumor progression from less aggressive subtypes to more aggressive states represent key targets for therapy. We identified a subset of Luminal A primary breast tumors to give rise to HER2-enriched (HER2E) subtype metastases, but remain clinically HER2 negative (cHER2-). By testing the unique genetic and transcriptomic features of these cases, we developed the hypothesis FGFR4 likely participates in this subtype switching. To evaluate this, we developed two FGFR4 genomic signatures using a PDX model treated with a FGFR4 inhibitor, which inhibited PDX growth in vivo. Bulk tumor gene expression analysis and single cell RNAseq demonstrated that the inhibition of FGFR4 signaling caused molecular switching. In the METABRIC breast cancer cohort,FGFR4-induced and FGFR4-repressed signatures each predicted overall survival. Additionally, FGFR4-induced signature was also an independent prognostic factor beyond subtype and stage. Supervised analysis of 77 primary tumors with paired metastasis revealed that the FGFR4-induced signature was significantly higher in luminal/ER+ tumor metastases compared with their primaries. Finally, multivariate analysis demonstrated that the FGFR4-induced signature also predicted site-specific metastasis for lung, liver and brain, but not for bone or lymph nodes. These data identify a link between FGFR4-regulated genes and metastasis, suggesting treatment options for FGFR4-positive patients, whose high expression is not caused by mutation or amplification.
Authors
Susana Garcia-Recio, Aatish Thennavan, Michael P. East, Joel S. Parker, Juan M. Cejalvo, Joseph P. Garay, Daniel P. Hollern, Xiaping He, Kevin R. Mott, Patricia Galván, Cheng Fan, Sara R. Selitsky, Alisha R. Coffey, David Marron, Fara Brasó-Maristany, Octavio Burgues, Joan Albanell, Federico Rojo, Ana Lluch, Eduardo Martinez de Dueñas, Jeffrey M. Rosen, Gary L. Johnson, Lisa A. Carey, Aleix Prat, Charles M. Perou
Abstract
Ligand-dependent activation of Hedgehog (Hh) signaling in cancer occurs without mutations in canonical pathway genes. Consequently, the genetic basis of Hh pathway activation in adult solid tumors, such as small-cell lung cancer (SCLC), is unknown. Here we show that combined inactivation of Trp53 and Rb1, a defining genetic feature of SCLC, leads to hypersensitivity to Hh ligand in vitro, and during neural tube development in vivo. This response is associated with the aberrant formation of primary cilia, an organelle essential for canonical Hh signaling through smoothened, a transmembrane protein targeted by small-molecule Hh inhibitors. We further show that loss of both Trp53 and Rb1 disables transcription of genes in the autophagic machinery necessary for the degradation of primary cilia. In turn, we also demonstrate a requirement for Kif3a, a gene essential for the formation of primary cilia, in a mouse model of SCLC induced by conditional deletion of both Trp53 and Rb1 in the adult airway. Our results provide a mechanistic framework for therapeutic targeting of ligand-dependent Hh signaling in human cancers with somatic mutations in both TP53 and RB1.
Authors
Catherine R. Cochrane, Vijesh Vaghjiani, Anette Szczepny, W. Samantha N. Jayasekara, Alvaro Gonzalez-Rajal, Kazu Kikuchi, Geoffrey W. McCaughan, Andrew Burgess, Daniel J. Gough, D. Neil Watkins, Jason E. Cain
Abstract
Chronic infections can lead to carcinogenesis through inflammation-related mechanisms. Chronic infection of the human gastric mucosa with Helicobacter pylori is a well-known risk factor for gastric cancer. However, the mechanisms underlying H. pylori–induced gastric carcinogenesis are incompletely defined. We aimed to screen and clarify the functions of long noncoding RNAs (lncRNAs) that are differentially expressed in H. pylori–related gastric cancer. We found that lncRNA SNHG17 was upregulated by H. pylori infection and markedly increased the levels of double-strand breaks (DSBs). SNHG17 overexpression correlated with poor overall survival in patients with gastric cancer. The recruitment of NONO by overabundant nuclear SNHG17, along with the role of cytoplasmic SNHG17 as a decoy for miR-3909, which regulates Rad51 expression, shifted the DSB repair balance from homologous recombination toward nonhomologous end joining. Notably, during chronic H. pylori infection, SNHG17 knockdown inhibited chromosomal aberrations. Our findings suggest that spatially independent deregulation of the SNHG17/NONO and SNHG17/miR-3909/RING1/Rad51 pathways upon H. pylori infection promotes tumorigenesis in gastric cancer by altering the DNA repair system, which is critical for the maintenance of genomic stability. Upregulation of SNHG17 by H. pylori infection might be an undefined link between cancer and inflammation.
Authors
Taotao Han, Xiaohui Jing, Jiayu Bao, Lianmei Zhao, Aidong Zhang, Renling Miao, Hui Guo, Baoguo Zhou, Shang Zhang, Jiazeng Sun, Juan Shi
Abstract
Peripheral neurotoxicity is a debilitating toxicity that afflicts up to 90% of patients with colorectal cancer receiving oxaliplatin-containing therapy. Although emerging evidence has highlighted the importance of various solute carriers to the toxicity of anticancer drugs, the contribution of these proteins to oxaliplatin-induced peripheral neurotoxicity remains controversial. Among candidate transporters investigated in genetically-engineered mouse models, we provide evidence for a critical role of the organic cation transporter 2 (OCT2) in satellite glial cells to oxaliplatin-induced neurotoxicity, and demonstrate that targeting OCT2 using genetic and pharmacological approaches ameliorates acute and chronic forms of neurotoxicity. The relevance of this transport system was verified in transporter-deficient rats as a secondary model organism, and translational significance of preventative strategies was demonstrated in preclinical models of colorectal cancer. These studies suggest that pharmacological targeting of OCT2 could be exploited to afford neuroprotection in cancer patients requiring treatment with oxaliplatin.
Authors
Kevin M. Huang, Alix F. Leblanc, Muhammad Erfan Uddin, Ji Young Kim, Mingqing Chen, Eric D. Eisenmann, Alice Gibson, Yang Li, Kristen W. Hong, Duncan DiGiacomo, Sherry Huinan Xia, Paola Alberti, Alessia Chiorazzi, Stephen N. Housley, Timothy C. Cope, Jason A. Sprowl, Jing Wang, Charles L. Loprinzi, Anne Noonan, Maryam Lustberg, Guido Cavaletti, Navjotsingh Pabla, Shuiying Hu, Alex Sparreboom
Abstract
γ9δ2T cells play a major role in cancer immune surveillance, yet the clinical translation of their in vitro promise remains challenging. To address limitations of previous clinical attempts utilizing expanded γ9δ2T cells, we explored the clonal diversity of γ9δ2T cell repertoires and characterized their target. We demonstrated that only a fraction of expanded γ9δ2T cells is active against cancer cells, and that activity of the parental clone, or functional avidity of selected γ9δ2TCRs does not associate with clonal frequency. We also analyzed the target-receptor-interface and provided a two-receptor, three-ligand model. Activation is initiated by binding of the γ9δ2TCR to BTN2A1 through the regions between CDR2 and CDR3 of the TCR γ chain, and modulated by the affinity of the CDR3 region of the TCR δ chain, which is phosphoantigen (pAg)-independent and does not depend on CD277. CD277 is secondary, serving as mandatory co-activating ligand. Binding of CD277 to its putative ligand does not depend on the presence of γ9δ2TCR, does depend on usage of the intracellular CD277, creates pAg-dependent proximity to BTN2A1, enhances cell-cell conjugate formation and stabilizes the immunological synapse. This process critically depends on the affinity of the γ9δ2TCR and requires membrane flexibility of the γ9δ2TCR and CD277, facilitating their polarization and high-density recruitment during immunological synapse formation.
Authors
Anna Vyborova, Dennis X. Beringer, Domenico Fasci, Froso Karaiskaki, Eline van Diest, Lovro Kramer, Aram de Haas, Jasper Sanders, Anke Janssen, Trudy Straetemans, Daniel Olive, Jeanette H.W. Leusen, Lola Boutin, Steven Nedellec, Samantha L. Schwartz, Michael J. Wester, Keith A. Lidke, Emmanuel Scotet, Diane Lidke, Albert J.R. Heck, Zsolt Sebestyen, Jurgen Kuball
Abstract
Graft-versus-host disease (GVHD) remains an important cause of morbidity and mortality after allogeneic hematopoietic cell transplantation (allo-HCT). For decades, GVHD prophylaxis has included calcineurin-inhibitors, despite their incomplete efficacy and impairment of graft-versus-leukemia (GVL). Distinct from pharmacologic immune suppression, we have developed a novel, human CD83-targeted chimeric antigen receptor (CAR) T cell for GVHD prevention. CD83 is expressed on allo-activated, conventional CD4+ T cells (Tconv) and proinflammatory dendritic cells (DC); which are both implicated in GVHD pathogenesis. Human CD83 CAR T cells eradicate pathogenic CD83+ target cells, significantly increase the ratio of regulatory T cells (Treg) to allo-activated Tconv, and provide durable prevention of xenogeneic GVHD. CD83 CAR T cells are also capable of treating xenogeneic GVHD. We show human, acute myeloid leukemia (AML) expresses CD83 and myeloid leukemia cell lines are readily killed by CD83 CAR T cells. Human CD83 CAR T cells are a promising cell-based approach to prevent two critical complications of allo-HCT; GVHD and relapse. Thus, human CD83 CAR T cells warrant clinical investigation in GVHD prevention and treatment, as well as targeting CD83+ AML.
Authors
Bishwas Shrestha, Kelly Walton, Jordan Reff, Elizabeth M. Sagatys, Nhan Tu, Justin C. Boucher, Gongbo Li, Tayyeb Ghafoor, Martin Felices, Jeffrey Miller, Joseph Pidala, Bruce R. Blazar, Claudio Anasetti, Brian C. Betts, Marco L. Davila
Abstract
Understanding tumor resistance to T cell immunotherapies is critical to improve patient outcomes. Our study revealed a role for transcriptional suppression of the tumor-intrinsic HLA class I (HLA-I) antigen processing and presentation machinery (APM) in therapy resistance. Low HLA-I APM mRNA levels in melanoma metastases prior to immune checkpoint blockade (ICB) correlated with non-responsiveness to therapy and poor clinical outcome. Patient-derived melanoma cells with silenced HLA-I APM escaped recognition by autologous CD8+ T cells. However, targeted activation of the innate immunoreceptor RIG-I initiated de novo HLA-I APM transcription thereby overcoming T cell resistance. Antigen presentation was restored in interferon (IFN)-sensitive but also immunoedited IFN-resistant melanoma models through RIG-I-dependent stimulation of an IFN-independent salvage pathway involving IRF1 and IRF3. Likewise, enhanced HLA-I APM expression was detected in RIG-I (DDX58)-high melanoma biopsies, correlating with improved patient survival. Induction of HLA-I APM by RIG-I synergized with antibodies blocking PD-1 and TIGIT inhibitory checkpoints in boosting the anti-tumor T cell activity of ICB non-responders. Overall, the herein identified IFN-independent effect of RIG-I on tumor antigen presentation and T cell recognition proposes innate immunoreceptor targeting as a strategy to overcome intrinsic T cell resistance of IFN-sensitive and IFN-resistant melanomas and improve clinical outcomes in immunotherapy.
Authors
Lina Such, Fang Zhao, Derek Liu, Beatrice Thier, Vu Thuy Khanh Le-Trilling, Antje Sucker, Christoph Coch, Natalia Pieper, Sebastian Howe, Hilal Bhat, Halime Kalkavan, Cathrin Ritter, Robin Brinkhaus, Selma Ugurel, Johannes Köster, Ulrike Seifert, Ulf Dittmer, Martin Schuler, Karl Sebastian Lang, Thomas A Kufer, Gunther Hartmann, Jürgen Christian Becker, Susanne Horn, Soldano Ferrone, David Liu, Eliezer M. Van Allen, Dirk Schadendorf, Klaus Griewank, Mirko Trilling, Annette Paschen
Abstract
Breast cancer stem cells (BCSCs) play a critical role in cancer recurrence and metastasis. Chemotherapy induces BCSC specification through increased expression of pluripotency factors, but how their expression is regulated is not fully understood. Here, we delineate a hypoxia-inducible factor 1 (HIF-1)-controlled pathway that epigenetically activates pluripotency factor gene transcription in response to chemotherapy. Paclitaxel induces HIF-1-dependent expression of S100A10, which forms a complex with ANXA2 that interacts with histone chaperone SPT6 and histone demethylase KDM6A. S100A10, ANXA2, SPT6, and KDM6A are recruited to OCT4 binding sites and KDM6A erases H3K27me3 chromatin marks, facilitating transcription of genes encoding the pluripotency factors NANOG, SOX2, and KLF4, which along with OCT4 are responsible for BCSC specification. Silencing of S100A10, ANXA2, SPT6, or KDM6A expression blocks chemotherapy-induced enrichment of BCSCs, impairs tumor initiation, and increases time to tumor recurrence after chemotherapy is discontinued. Pharmacological inhibition of KDM6A also impairs chemotherapy-induced BCSC enrichment. These results suggest that targeting HIF-1/S100A10-dependent and KDM6A-mediated epigenetic activation of pluripotency factor gene expression in combination with chemotherapy may block BCSC enrichment and improve clinical outcome.
Authors
Haiquan Lu, Yangyiran Xie, Linh Tran, Jie Lan, Yongkang Yang, Naveena L. Murugan, Ru Wang, Yueyang J. Wang, Gregg L. Semenza
Abstract
Despite widespread use of taxanes, mechanisms of action and resistance in vivo remain to be established, and there is no way of predicting who will respond to therapy. This study examined prostate cancer (PCa) xenografts and patient samples to identify in vivo mechanisms of taxane action and resistance. Docetaxel drug-target engagement was assessed by confocal anti-tubulin immunofluorescence to quantify microtubule bundling in interphase cells and aberrant mitoses. Tumor biopsies from metastatic PCa patients obtained 2 to 5 days after their first dose of docetaxel or cabazitaxel were processed to assess microtubule bundling, which correlated with clinical response. Microtubule bundling was evident in PCa xenografts 2 to 3 days after docetaxel treatment but was decreased or lost with acquired resistance. Biopsies after treatment with leuprolide plus docetaxel showed extensive microtubule bundling as did biopsies obtained 2 to 3 days after initiation of docetaxel or cabazitaxel in 2 patients with castration-resistant PCa with clinical responses. In contrast, microtubule bundling in biopsies 2 to 3 days after the first dose of docetaxel was markedly lower in 4 nonresponding patients. These findings indicate that taxanes target both mitotic and interphase cells in vivo and that resistance is through mechanisms that impair drug-target engagement. Moreover, the findings suggest that microtubule bundling after initial taxane treatment may be a predictive biomarker for clinical response.
Authors
Ada Gjyrezi, Fang Xie, Olga Voznesensky, Prateek Khanna, Carla Calagua, Yang Bai, Justin Kung, Jim Wu, Eva Corey, Bruce Montgomery, Sandrine Mace, Diego A. Gianolio, Glenn J. Bubley, Steven P. Balk, Paraskevi Giannakakou, Rupal S. Bhatt
Abstract
Phosphoglycerate dehydrogenase (PHGDH), the first rate-limiting enzyme of serine synthesis, is frequently overexpressed in human cancer. PHGDH overexpression activates serine synthesis to promote cancer progression. Currently, PHGDH regulation in normal cells and cancer is not well understood. Parkin, an E3 ubiquitin ligase involved in Parkinson’s disease, is a tumor suppressor. Parkin expression is frequently downregulated in many types of cancer, and its tumor-suppressive mechanism is poorly defined. Here, we show that PHGDH is a substrate for Parkin-mediated ubiquitination and degradation. Parkin interacted with PHGDH and ubiquitinated PHGDH at lysine 330, leading to PHGDH degradation to suppress serine synthesis. Parkin deficiency in cancer cells stabilized PHGDH and activated serine synthesis to promote cell proliferation and tumorigenesis, which was largely abolished by targeting PHGDH with RNA interference, CRISPR/Cas9 KO, or small-molecule PHGDH inhibitors. Furthermore, Parkin expression was inversely correlated with PHGDH expression in human breast cancer and lung cancer. Our results revealed PHGDH ubiquitination by Parkin as a crucial mechanism for PHGDH regulation that contributes to the tumor-suppressive function of Parkin and identified Parkin downregulation as a critical mechanism underlying PHGDH overexpression in cancer.
Authors
Juan Liu, Cen Zhang, Hao Wu, Xiao-Xin Sun, Yanchen Li, Shan Huang, Xuetian Yue, Shou-En Lu, Zhiyuan Shen, Xiaoyang Su, Eileen White, Bruce G. Haffty, Wenwei Hu, Zhaohui Feng
Copyright © 2020 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)