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Cancer Research
Journal Prestige (SJR): 4.26
Citation Impact (citeScore): 7
Number of Followers: 67  
 
  Hybrid Journal Hybrid journal (It can contain Open Access articles)
ISSN (Print) 0008-5472 - ISSN (Online) 1538-7445
Published by AACR Homepage  [8 journals]
  • Highlights from Recent Cancer Literature

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      Pages: 4887 - 4888
      PubDate: 2021-10-01T00:05:31-07:00
      DOI: 10.1158/0008-5472.CAN-81-19-BI
      Issue No: Vol. 81, No. 19 (2021)
       
  • Effects of Exercise on Cancer Treatment Efficacy: A Systematic Review of
           Preclinical and Clinical Studies

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      Authors: Lin Yang; Andria R. Morielli, Emily Heer, Amy A. Kirkham, Winson Y. Cheung, Nawaid Usmani, Christine M. Friedenreich, Kerry S. Courneya
      Pages: 4889 - 4895
      Abstract: We systematically reviewed and synthesized evidence on the impact of physical activity/exercise on cancer treatment efficacy. We included six preclinical and seven clinical studies. Exercise significantly enhanced the efficacy of chemotherapy and tamoxifen in seven of eight rodent models in either an additive, sensitizing, or synergistic manner. In clinical studies, preliminary evidence indicates that exercise during neoadjuvant, primary, and adjuvant treatment may enhance efficacy of cancer therapies; however, no clinical study was designed for this purpose. Here we discuss the biological mechanisms of exercise-associated enhancement of therapeutic efficacy and propose future research directions to definitively examine the effects of exercise on cancer treatment and patient outcomes.
      PubDate: 2021-10-01T00:05:31-07:00
      DOI: 10.1158/0008-5472.CAN-21-1258
      Issue No: Vol. 81, No. 19 (2021)
       
  • Cancer Signaling Drives Cancer Metabolism: AKT and the Warburg Effect

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      Authors: Aaron M. Hosios; Brendan D. Manning
      Pages: 4896 - 4898
      Abstract: The Warburg effect, the propensity of some cells to metabolize glucose to lactate in the presence of oxygen (also known as aerobic glycolysis), has long been observed in cancer and other contexts of cell proliferation, but only in the past two decades have significant gains been made in understanding how and why this metabolic transformation occurs. In 2004, Cancer Research published a study by Elstrom and colleagues that provided one of the first connections between a specific oncogene and aerobic glycolysis. Studying hematopoietic and glioblastoma cell lines, they demonstrated that constitutive activation of AKT promotes an increased glycolytic rate without altering proliferation or oxygen consumption in culture. They proposed that it is this effect that allows constitutive AKT activation to transform cells and found that it sensitizes cells to glucose deprivation. In the years since, mechanistic understanding of oncogenic control of metabolism, and glycolysis specifically, has deepened substantially. Current work seeks to understand the benefits and liabilities associated with glycolytic metabolism and to identify inhibitors that might be of clinical benefit to target glycolytic cancer cells.See related article by Elstrom and colleagues, Cancer Res 2004;64:3892–9
      PubDate: 2021-10-01T00:05:31-07:00
      DOI: 10.1158/0008-5472.CAN-21-2647
      Issue No: Vol. 81, No. 19 (2021)
       
  • A Novel Long Noncoding RNA Finetunes the DNA Damage Response in
           Hepatocellular Carcinoma

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      Authors: Marina Barcena-Varela; Amaia Lujambio
      Pages: 4899 - 4900
      Abstract: The study by Unfried and colleagues reports the intriguing discovery of a novel long noncoding RNA (lncRNA) with a critical role in the regulation of DNA damage response in hepatocellular carcinoma. Providing an exhaustive and detailed characterization of the complex network interactions within the double-stranded breaks in the DNA, the authors demonstrated that NIHCOLE serves as a scaffold and facilitator of nonhomologous end-joining machinery. This study greatly contributes to the growing evidence supporting the key roles of ncRNAs in health and disease. Although larger studies are needed to understand the potential of lncRNAs to improve the clinical management of patients with cancer, this study demonstrates that high expression of NIHCOLE may be associated with an impaired response to DNA damage–based therapies, in part through its role in preventing cell death.See related article by Unfried et al., p. 4910
      PubDate: 2021-10-01T00:05:31-07:00
      DOI: 10.1158/0008-5472.CAN-21-2776
      Issue No: Vol. 81, No. 19 (2021)
       
  • Subclone Eradication Analysis Identifies Targets for Enhanced Cancer
           Therapy and Reveals L1 Retrotransposition as a Dynamic Source of Cancer
           Heterogeneity

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      Authors: Kirsi Ketola; Heidi Kalȷunen, Sinȷa Taavitsainen, Roosa Kaariȷarvi, Emmi Jarvela, Bernardo Rodriguez–Martin, Kerstin Haase, Dan J. Woodcock, Jose Tubio, David C. Wedge, Matti Nykter, G. Steven Bova
      Pages: 4901 - 4909
      Abstract: Treatment-eradicated cancer subclones have been reported in leukemia and have recently been detected in solid tumors. Here we introduce Differential Subclone Eradication and Resistance (DSER) analysis, a method developed to identify molecular targets for improved therapy by direct comparison of genomic features of eradicated and resistant subclones in pre- and posttreatment samples from a patient with BRCA2-deficient metastatic prostate cancer. FANCI and EYA4 were identified as candidate DNA repair–related targets for converting subclones from resistant to eradicable, and RNAi-mediated depletion of FANCI confirmed it as a potential target. The EYA4 alteration was associated with adjacent L1 transposon insertion during cancer evolution upon treatment, raising questions surrounding the role of therapy in L1 activation. Both carboplatin and enzalutamide turned on L1 transposon machinery in LNCaP and VCaP but not in PC3 and 22Rv1 prostate cancer cell lines. L1 activation in LNCaP and VCaP was inhibited by the antiretroviral drug azidothymidine. L1 activation was also detected postcastration in LuCaP 77 and LuCaP 105 xenograft models and postchemotherapy in previously published time-series transcriptomic data from SCC25 head and neck cancer cells. In conclusion, DSER provides an informative intermediate step toward effective precision cancer medicine and should be tested in future studies, especially those including dramatic but temporary metastatic tumor regression. L1 transposon activation may be a modifiable source of cancer genomic heterogeneity, suggesting the potential of leveraging newly discovered triggers and blockers of L1 activity to overcome therapy resistance.Significance:Differential analysis of eradicated and resistant subclones following cancer treatment identifies that L1 activity associated with resistance is induced by current therapies and blocked by the antiretroviral drug azidothymidine.
      PubDate: 2021-10-01T00:05:31-07:00
      DOI: 10.1158/0008-5472.CAN-21-0371
      Issue No: Vol. 81, No. 19 (2021)
       
  • Long Noncoding RNA NIHCOLE Promotes Ligation Efficiency of DNA
           Double-Strand Breaks in Hepatocellular Carcinoma

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      Authors: Juan P. Unfried; Mikel Marin–Baquero, Angel Rivera–Calzada, Nerea Razquin, Eva M. Martin–Cuevas, Sara de Braganca, Clara Aicart–Ramos, Christopher McCoy, Laura Prats–Mari, Raquel Arribas–Bosacoma, Linda Lee, Stefano Caruso, Jessica Zucman–Rossi, Bruno Sangro, Gareth Williams, Fernando Moreno–Herrero, Oscar Llorca, Susan P. Lees–Miller, Puri Fortes
      Pages: 4910 - 4925
      Abstract: Long noncoding RNAs (lncRNA) are emerging as key players in cancer as parts of poorly understood molecular mechanisms. Here, we investigated lncRNAs that play a role in hepatocellular carcinoma (HCC) and identified NIHCOLE, a novel lncRNA induced in HCC with oncogenic potential and a role in the ligation efficiency of DNA double-stranded breaks (DSB). NIHCOLE expression was associated with poor prognosis and survival of HCC patients. Depletion of NIHCOLE from HCC cells led to impaired proliferation and increased apoptosis. NIHCOLE deficiency led to accumulation of DNA damage due to a specific decrease in the activity of the nonhomologous end-joining (NHEJ) pathway of DSB repair. DNA damage induction in NIHCOLE-depleted cells further decreased HCC cell growth. NIHCOLE was associated with DSB markers and recruited several molecules of the Ku70/Ku80 heterodimer. Further, NIHCOLE putative structural domains supported stable multimeric complexes formed by several NHEJ factors including Ku70/80, APLF, XRCC4, and DNA ligase IV. NHEJ reconstitution assays showed that NIHCOLE promoted the ligation efficiency of blunt-ended DSBs. Collectively, these data show that NIHCOLE serves as a scaffold and facilitator of NHEJ machinery and confers an advantage to HCC cells, which could be exploited as a targetable vulnerability.Significance:This study characterizes the role of lncRNA NIHCOLE in DNA repair and cellular fitness in HCC, thus implicating it as a therapeutic target.See related commentary by Barcena-Varela and Lujambio, p. 4899
      PubDate: 2021-10-01T00:05:31-07:00
      DOI: 10.1158/0008-5472.CAN-21-0463
      Issue No: Vol. 81, No. 19 (2021)
       
  • The Evolving Genomic Landscape of Esophageal Squamous Cell Carcinoma Under
           Chemoradiotherapy

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      Authors: Hidenari Hirata; Atsushi Niida, Nobuyuki Kakiuchi, Ryutaro Uchi, Keishi Sugimachi, Takaaki Masuda, Tomoko Saito, Shun-Ichiro Kageyama, Yushi Motomura, Shuhei Ito, Tadamasa Yoshitake, Daisuke Tsurumaru, Yusuke Nishimuta, Akira Yokoyama, Takanori Hasegawa, Kenichi Chiba, Yuichi Shiraishi, Junyan Du, Fumihito Miura, Masaru Morita, Yasushi Toh, Masakazu Hirakawa, Yoshiyuki Shioyama, Takashi Ito, Tetsuo Akimoto, Satoru Miyano, Tatsuhiro Shibata, Masaki Mori, Yutaka Suzuki, Seishi Ogawa, Kousei Ishigami, Koshi Mimori
      Pages: 4926 - 4938
      Abstract: Esophageal squamous cell carcinoma (ESCC) often recurs after chemoradiotherapy, and the prognosis of ESCC after chemoradiotherapy has not improved over the past few decades. The mutation process in chemoradiotherapy-resistant clones and the functional relevance of genetic alterations remain unclear. To address these problems, we performed whole-exome sequencing of 52 tumor samples from 33 patients with ESCC who received radiotherapy combined with 5-fluorouracil/platinum. In multiregion analyses of pretreatment and locally recurrent lesions from five cases, most driver gene-altered clones remained under chemoradiotherapy selection pressure, while few driver gene alterations were acquired at recurrence. The mutation signatures of recurrent ESCC, including increased deletion frequency and platinum dose-dependent base substitution signatures, were substantially different from those of primary ESCC and reflected the iatrogenic impacts of chemoradiotherapy. Single-region analysis of 28 pretreatment tumors indicated that focal copy-number gain at the MYC locus was significantly associated with poor progression-free survival and overall survival after chemoradiotherapy. MYC gain remained throughout the chemoradiotherapy course and potentially contributes to intrinsic resistance to chemoradiotherapy. Consistent with these findings, MYC copy number and mRNA and protein levels in ESCC cell lines correlated positively with resistance to radiotherapy, and MYC knockdown improved sensitivity to radiotherapy. Overall, these data characterize the clonal evolution process induced by chemoradiotherapy and clinically relevant associations for genetic alterations in ESCC. These findings increase our understanding of therapeutic resistance and support the rationale for precision chemoradiotherapy.Significance:Whole-exome sequencing reveals the genetic evolution of ESCC during chemoradiotherapy, highlighting MYC gain in pretreatment tumors as a potential marker of therapy resistance.
      PubDate: 2021-10-01T00:05:31-07:00
      DOI: 10.1158/0008-5472.CAN-21-0653
      Issue No: Vol. 81, No. 19 (2021)
       
  • Radiation-Induced Phosphorylation of a Prion-Like Domain Regulates
           Transformation by FUS-CHOP

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      Authors: Mark Chen; Joseph P. Foster II, Ian C. Lock, Nathan H. Leisenring, Andrea R. Daniel, Warren Floyd, Eric Xu, Ian J. Davis, David G. Kirsch
      Pages: 4939 - 4948
      Abstract: Chromosomal translocations generate oncogenic fusion proteins in approximately one-third of sarcomas, but how these proteins promote tumorigenesis is not well understood. Interestingly, some translocation-driven cancers exhibit dramatic clinical responses to therapy, such as radiotherapy, although the precise mechanism has not been elucidated. Here we reveal a molecular mechanism by which the fusion oncoprotein FUS-CHOP promotes tumor maintenance that also explains the remarkable sensitivity of myxoid liposarcomas to radiation therapy. FUS-CHOP interacted with chromatin remodeling complexes to regulate sarcoma cell proliferation. One of these chromatin remodelers, SNF2H, colocalized with FUS-CHOP genome-wide at active enhancers. Following ionizing radiation, DNA damage response kinases phosphorylated the prion-like domain of FUS-CHOP to impede these protein–protein interactions, which are required for transformation. Therefore, the DNA damage response after irradiation disrupted oncogenic targeting of chromatin remodelers required for FUS-CHOP–driven sarcomagenesis. This mechanism of disruption links phosphorylation of the prion-like domain of an oncogenic fusion protein to DNA damage after ionizing radiation and reveals that a dependence on oncogenic chromatin remodeling underlies sensitivity to radiation therapy in myxoid liposarcoma.Significance:Prion-like domains, which are frequently translocated in cancers as oncogenic fusion proteins that drive global epigenetic changes, confer sensitivity to radiation via disruption of oncogenic interactions.
      PubDate: 2021-10-01T00:05:31-07:00
      DOI: 10.1158/0008-5472.CAN-20-1497
      Issue No: Vol. 81, No. 19 (2021)
       
  • Hypoxia Promotes Breast Cancer Cell Growth by Activating a Glycogen
           Metabolic Program

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      Authors: Ke Tang; Liyan Zhu, Jie Chen, Dianheng Wang, Liping Zeng, Chen Chen, Liang Tang, Li Zhou, Keke Wei, Yabo Zhou, Jiadi Lv, Yuying Liu, Huafeng Zhang, Jingwei Ma, Bo Huang
      Pages: 4949 - 4963
      Abstract: Hypoxia is known to be commonly present in breast tumor microenvironments. Stem-like cells that repopulate breast tumors, termed tumor-repopulating cells (TRC), thrive under hypoxic conditions, but the underlying mechanism remains unclear. Here, we show that hypoxia promotes the growth of breast TRCs through metabolic reprogramming. Hypoxia mobilized transcription factors HIF1α and FoxO1 and induced epigenetic reprogramming to upregulate cytosolic phosphoenolpyruvate carboxykinase (PCK1), a key enzyme that initiates gluconeogenesis. PCK1 subsequently triggered retrograde carbon flow from gluconeogenesis to glycogenesis, glycogenolysis, and the pentose phosphate pathway. The resultant NADPH facilitated reduced glutathione production, leading to a moderate increase of reactive oxygen species that stimulated hypoxic breast TRC growth. Notably, this metabolic mechanism was absent in differentiated breast tumor cells. Targeting PCK1 synergized with paclitaxel to reduce the growth of triple-negative breast cancer (TNBC). These findings uncover an altered glycogen metabolic program in breast cancer, providing potential metabolic strategies to target hypoxic breast TRCs and TNBC.Significance:Hypoxic breast cancer cells trigger self-growth through PCK1-mediated glycogen metabolism reprogramming that leads to NADPH production to maintain a moderate ROS level.
      PubDate: 2021-10-01T00:05:31-07:00
      DOI: 10.1158/0008-5472.CAN-21-0753
      Issue No: Vol. 81, No. 19 (2021)
       
  • MTAP Deficiency-Induced Metabolic Reprogramming Creates a Vulnerability to
           Cotargeting De Novo Purine Synthesis and Glycolysis in Pancreatic Cancer

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      Authors: Qiangsheng Hu; Yi Qin, Shunrong Ji, Xiuhui Shi, Weixing Dai, Guixiong Fan, Shuo Li, Wenyan Xu, Wensheng Liu, Mengqi Liu, Zheng Zhang, Zeng Ye, Zhijun Zhou, Jingxuan Yang, Qifeng Zhuo, Xianjun Yu, Min Li, Xiaowu Xu
      Pages: 4964 - 4980
      Abstract: Methylthioadenosine phosphorylase (MTAP) is a key enzyme associated with the salvage of methionine and adenine that is deficient in 20% to 30% of pancreatic cancer. Our previous study revealed that MTAP deficiency indicates a poor prognosis for patients with pancreatic ductal adenocarcinoma (PDAC). In this study, bioinformatics analysis of The Cancer Genome Atlas (TCGA) data indicated that PDACs with MTAP deficiency display a signature of elevated glycolysis. Metabolomics studies showed that that MTAP deletion–mediated metabolic reprogramming enhanced glycolysis and de novo purine synthesis in pancreatic cancer cells. Western blot analysis revealed that MTAP knockout stabilized hypoxia-inducible factor 1α (HIF1α) protein via posttranslational phosphorylation. RIO kinase 1 (RIOK1), a downstream kinase upregulated in MTAP-deficient cells, interacted with and phosphorylated HIF1α to regulate its stability. In vitro experiments demonstrated that the glycolysis inhibitor 2-deoxy-d-glucose (2-DG) and the de novo purine synthesis inhibitor l-alanosine synergized to kill MTAP-deficient pancreatic cancer cells. Collectively, these results reveal that MTAP deficiency drives pancreatic cancer progression by inducing metabolic reprogramming, providing a novel target and therapeutic strategy for treating MTAP-deficient disease.Significance:This study demonstrates that MTAP status impacts glucose and purine metabolism, thus identifying multiple novel treatment options against MTAP-deficient pancreatic cancer.
      PubDate: 2021-10-01T00:05:31-07:00
      DOI: 10.1158/0008-5472.CAN-20-0414
      Issue No: Vol. 81, No. 19 (2021)
       
  • Lipidomic Profiling of Clinical Prostate Cancer Reveals Targetable
           Alterations in Membrane Lipid Composition

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      Authors: Lisa M. Butler; Chui Yan Mah, Jelle Machiels, Andrew D. Vincent, Swati Irani, Shadrack M. Mutuku, Xander Spotbeen, Muralidhararao Bagadi, David Waltregny, Max Moldovan, Jonas Dehairs, Frank Vanderhoydonc, Katarzyna Bloch, Rajdeep Das, Jurgen Stahl, James G. Kench, Thomas Gevaert, Rita Derua, Etienne Waelkens, Zeyad D. Nassar, Luke A. Selth, Paul J. Trim, Marten F. Snel, David J. Lynn, Wayne D. Tilley, Lisa G. Horvath, Margaret M. Centenera, Johannes V. Swinnen
      Pages: 4981 - 4993
      Abstract: Dysregulated lipid metabolism is a prominent feature of prostate cancer that is driven by androgen receptor (AR) signaling. Here we used quantitative mass spectrometry to define the “lipidome” in prostate tumors with matched benign tissues (n = 21), independent unmatched tissues (n = 47), and primary prostate explants cultured with the clinical AR antagonist enzalutamide (n = 43). Significant differences in lipid composition were detected and spatially visualized in tumors compared with matched benign samples. Notably, tumors featured higher proportions of monounsaturated lipids overall and elongated fatty acid chains in phosphatidylinositol and phosphatidylserine lipids. Significant associations between lipid profile and malignancy were validated in unmatched samples, and phospholipid composition was characteristically altered in patient tissues that responded to AR inhibition. Importantly, targeting tumor-related lipid features via inhibition of acetyl-CoA carboxylase 1 significantly reduced cellular proliferation and induced apoptosis in tissue explants. This characterization of the prostate cancer lipidome in clinical tissues reveals enhanced fatty acid synthesis, elongation, and desaturation as tumor-defining features, with potential for therapeutic targeting.Significance:This study identifies malignancy and treatment-associated changes in lipid composition of clinical prostate cancer tissues, suggesting that mediators of these lipidomic changes could be targeted using existing metabolic agents.
      PubDate: 2021-10-01T00:05:31-07:00
      DOI: 10.1158/0008-5472.CAN-20-3863
      Issue No: Vol. 81, No. 19 (2021)
       
  • Unraveling Ewing Sarcoma Tumorigenesis Originating from Patient-Derived
           Mesenchymal Stem Cells

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      Authors: Anna Sole; Sandrine Grossetete, Maxime Heintze, Loelia Babin, Sakina Zaidi, Patrick Revy, Benȷamin Renouf, Anne De Cian, Carine Giovannangeli, Cecile Pierre–Eugene, Isabelle Janoueix–Lerosey, Lucile Couronne, Sophie Kaltenbach, Mark Tomishima, Maria Jasin, Thomas G.P. Grunewald, Olivier Delattre, Didier Surdez, Erika Brunet
      Pages: 4994 - 5006
      Abstract: Ewing sarcoma is characterized by pathognomonic translocations, most frequently fusing EWSR1 with FLI1. An estimated 30% of Ewing sarcoma tumors also display genetic alterations in STAG2, TP53, or CDKN2A (SPC). Numerous attempts to develop relevant Ewing sarcoma models from primary human cells have been unsuccessful in faithfully recapitulating the phenotypic, transcriptomic, and epigenetic features of Ewing sarcoma. In this study, by engineering the t(11;22)(q24;q12) translocation together with a combination of SPC mutations, we generated a wide collection of immortalized cells (EWIma cells) tolerating EWSR1-FLI1 expression from primary mesenchymal stem cells (MSC) derived from a patient with Ewing sarcoma. Within this model, SPC alterations strongly favored Ewing sarcoma oncogenicity. Xenograft experiments with independent EWIma cells induced tumors and metastases in mice, which displayed bona fide features of Ewing sarcoma. EWIma cells presented balanced but also more complex translocation profiles mimicking chromoplexy, which is frequently observed in Ewing sarcoma and other cancers. Collectively, these results demonstrate that bone marrow–derived MSCs are a source of origin for Ewing sarcoma and also provide original experimental models to investigate Ewing sarcomagenesis.Significance:These findings demonstrate that Ewing sarcoma can originate from human bone-marrow–derived mesenchymal stem cells and that recurrent mutations support EWSR1-FLI1 translocation-mediated transformation.
      PubDate: 2021-10-01T00:05:31-07:00
      DOI: 10.1158/0008-5472.CAN-20-3837
      Issue No: Vol. 81, No. 19 (2021)
       
  • AMBRA1 Promotes TGF{beta} Signaling via Nonproteolytic Polyubiquitylation
           of Smad4

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      Authors: Jinquan Liu; Bo Yuan, Jin Cao, Hongjie Luo, Shuchen Gu, Mengdi Zhang, Ran Ding, Long Zhang, Fangfang Zhou, Mien-Chie Hung, Pinglong Xu, Xia Lin, Jianping Jin, Xin-Hua Feng
      Pages: 5007 - 5020
      Abstract: Transforming growth factor β (TGFβ) is prometastatic in advanced cancers and its biological activities are mainly mediated by the Smad family of proteins. Smad4 is the central signal transducer and transcription factor in the TGFβ pathway, yet the underlying mechanisms that govern transcriptional activities of Smad4 are not fully understood. Here, we show that AMBRA1, a member of the DDB1 and CUL4-associated factor (DCAF) family of proteins, serves as the substrate receptor for Smad4 in the CUL4-RING (CRL4) ubiquitin ligase complex. The CRL4-AMBRA1 ubiquitin ligase mediates nonproteolytic polyubiquitylation of Smad4 to enhance its transcriptional functions. Consequently, AMBRA1 potentiated TGFβ signaling and critically promoted TGFβ-induced epithelial-to-mesenchymal transition, migration, and invasion of breast cancer cells. Mouse models of breast cancer demonstrated that AMBRA1 promotes metastasis. Collectively, these results show that CRL4-AMBRA1 facilitates TGFβ-driven metastasis by increasing Smad4 polyubiquitylation, suggesting AMBRA1 may serve as a new therapeutic target in metastatic breast cancer.Significance:This study identifies AMBRA1 as a novel regulator of TGFβ signaling and breast cancer metastasis, supporting further exploration of AMBRA1 as a target for cancer therapy.
      PubDate: 2021-10-01T00:05:31-07:00
      DOI: 10.1158/0008-5472.CAN-21-0431
      Issue No: Vol. 81, No. 19 (2021)
       
  • The CD200-CD200R Axis Promotes Squamous Cell Carcinoma Metastasis via
           Regulation of Cathepsin K

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      Authors: Iasha Z. Khan; Christina A. Del Guzzo, Anqi Shao, Jiyoon Cho, Rong Du, Adrienne O. Cohen, David M. Owens
      Pages: 5021 - 5032
      Abstract: The CD200–CD200R immunoregulatory signaling axis plays an etiologic role in the survival and spread of numerous cancers, primarily through suppression of antitumor immune surveillance. Our previous work outlined a prometastatic role for the CD200–CD200R axis in cutaneous squamous cell carcinoma (cSCC) that is independent of direct T-cell suppression but modulates the function of infiltrating myeloid cells. To identify effectors of the CD200–CD200R axis important for cSCC metastasis, we conducted RNA sequencing profiling of infiltrating CD11B+Cd200R+ cells isolated from CD200+ versus CD200-null cSCCs and identified the cysteine protease cathepsin K (Ctsk) to be highly upregulated in CD200+ cSCCs. CD11B+Cd200R+ cells expressed phenotypic markers associated with myeloid-derived suppressor cell–like cells and tumor-associated macrophages and were the primary source of Ctsk expression in cSCC. A Cd200R+ myeloid cell–cSCC coculture system showed that induction of Ctsk was dependent on engagement of the CD200–CD200R axis, indicating that Ctsk is a target gene of this pathway in the cSCC tumor microenvironment. Inhibition of Ctsk, but not matrix metalloproteinases, significantly blocked cSCC cell migration in vitro. Finally, targeted CD200 disruption in tumor cells and Ctsk pharmacologic inhibition significantly reduced cSCC metastasis in vivo. Collectively, these findings support the conclusion that CD200 stimulates cSCC invasion and metastasis via induction of Ctsk in CD200R+ infiltrating myeloid cells.Significance:These findings highlight the relationship between CD200–CD200R and cathepsin K in cutaneous squamous cell carcinoma metastasis and suggest that either of these components may serve as a viable therapeutic target in this disease.
      PubDate: 2021-10-01T00:05:31-07:00
      DOI: 10.1158/0008-5472.CAN-20-3251
      Issue No: Vol. 81, No. 19 (2021)
       
  • Mutant Idh2 Cooperates with a NUP98-HOXD13 Fusion to Induce Early Immature
           Thymocyte Precursor ALL

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      Authors: Liat Goldberg; Vijay Negi, Yang Jo Chung, Masahiro Onozawa, Yuelin J. Zhu, Robert L. Walker, Rachel Pierce, Daxesh P. Patel, Kristopher W. Krausz, Frank J. Gonzalez, Margaret A. Goodell, Benjamin A.T. Rodriguez, Paul S. Meltzer, Peter D. Aplan
      Pages: 5033 - 5046
      Abstract: Mutations in the isocitrate dehydrogenase 1 (IDH1) and IDH2 genes are frequently observed in a wide variety of hematologic malignancies, including myeloid and T-cell leukemias. In this study, we generated Idh2R140Q transgenic mice to examine the role of the Idh2R140Q mutation in leukemia. No leukemia developed in Idh2R140Q transgenic mice, suggesting a need for additional genetic events for leukemia development. Because myeloid cells from NUP98-HOXD13 fusion (NHD13) transgenic mice frequently acquire somatic Idh mutations when they transform to acute myeloid leukemia, we generated Idh2R140Q/NHD13 double transgenic mice. Idh2R140Q/NHD13 transgenic mice developed an immature T-cell leukemia with an immunophenotype similar to double-negative 1 (DN1) or DN2 thymocytes. Idh2R140Q/NHD13 leukemic cells were enriched for an early thymic precursor transcriptional signature, and the gene expression profile for Idh2R140Q/NHD13 DN1/DN2 T-ALL closely matched that of human early/immature T-cell precursor (EITP) acute lymphoblastic leukemia (ALL). Moreover, recurrent mutations found in patients with EITP ALL, including KRAS, PTPN11, JAK3, SH2B3, and EZH2 were also found in Idh2R140Q/NHD13 DN1/DN2 T-ALL. In vitro treatment of Idh2R140Q/NHD13 thymocytes with enasidenib, a selective inhibitor of mutant IDH2, led to a marked decrease in leukemic cell proliferation. These findings demonstrate that Idh2R140Q/NHD13 mice can serve as a useful in vivo model for the study of early/immature thymocyte precursor acute lymphoblastic leukemia development and therapy.Significance:T-cell leukemia induced in Idh2R140Q/NUP98-HOXD13 mice is immunophenotypically, transcriptionally, and genetically similar to human EITP ALL, providing a model for studying disease development and treatment.
      PubDate: 2021-10-01T00:05:31-07:00
      DOI: 10.1158/0008-5472.CAN-21-1027
      Issue No: Vol. 81, No. 19 (2021)
       
  • Neuroblastoma Formation Requires Unconventional CD4 T Cells and
           Arginase-1-Dependent Myeloid Cells

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      Authors: Lee-Ann Van de Velde; E. Kaitlynn Allen, Jeremy Chase Crawford, Taylor L. Wilson, Clifford S. Guy, Marion Russier, Leonie Zeitler, Armita Bahrami, David Finkelstein, Stephane Pelletier, Stacey Schultz-Cherry, Paul G. Thomas, Peter J. Murray
      Pages: 5047 - 5059
      Abstract: Immune cells regulate tumor growth by mirroring their function as tissue repair organizers in normal tissues. To understand the different facets of immune–tumor collaboration through genetics, spatial transcriptomics, and immunologic manipulation with noninvasive, longitudinal imaging, we generated a penetrant double oncogene–driven autochthonous model of neuroblastoma. Spatial transcriptomic analysis showed that CD4+ and myeloid populations colocalized within the tumor parenchyma, while CD8+ T cells and B cells were peripherally dispersed. Depletion of CD4+ T cells or CCR2+ macrophages, but not B cells, CD8+ T cells, or natural killer (NK) cells, prevented tumor formation. Tumor CD4+ T cells displayed unconventional phenotypes and were clonotypically diverse and antigen independent. Within the myeloid fraction, tumor growth required myeloid cells expressing arginase-1. Overall, these results demonstrate how arginine-metabolizing myeloid cells conspire with pathogenic CD4+ T cells to create permissive conditions for tumor formation, suggesting that these protumorigenic pathways could be disabled by targeting myeloid arginine metabolism.Significance:A new model of human neuroblastoma provides ways to track tumor formation and expansion in living animals, allowing identification of CD4+ T-cell and macrophage functions required for oncogenesis.
      PubDate: 2021-10-01T00:05:31-07:00
      DOI: 10.1158/0008-5472.CAN-21-0691
      Issue No: Vol. 81, No. 19 (2021)
       
  • Endothelial Reprogramming Stimulated by Oncostatin M Promotes Inflammation
           and Tumorigenesis in VHL-Deficient Kidney Tissue

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      Authors: Hieu-Huy Nguyen-Tran; Thi-Ngoc Nguyen, Chen-Yun Chen, Tien Hsu
      Pages: 5060 - 5073
      Abstract: Clear-cell renal cell carcinoma (ccRCC) is the most prevalent subtype of renal cell carcinoma (RCC), and its progression has been linked to chronic inflammation. About 70% of the ccRCC cases are associated with inactivation of the von Hippel–Lindau (VHL) tumor-suppressor gene. However, it is still not clear how mutations in VHL, encoding the substrate-recognition subunit of an E3 ubiquitin ligase that targets the alpha subunit of hypoxia-inducible factor-α (HIFα), can coordinate tissue inflammation and tumorigenesis. We previously generated mice with conditional Vhlh knockout in kidney tubules, which resulted in severe inflammation and fibrosis in addition to hyperplasia and the appearance of transformed clear cells. Interestingly, the endothelial cells (EC), although not subject to genetic manipulation, nonetheless showed profound changes in gene expression that suggest a role in promoting inflammation and tumorigenesis. Oncostatin M (OSM) mediated the interaction between VHL-deficient renal tubule cells and the ECs, and the activated ECs in turn induced macrophage recruitment and polarization. The OSM-dependent microenvironment also promoted metastasis of exogenous tumors. Thus, OSM signaling initiates reconstitution of an inflammatory and tumorigenic microenvironment by VHL-deficient renal tubule cells, which plays a critical role in ccRCC initiation and progression.Significance:A novel mechanism of cross-talk between ECs and VHL-deficient kidney tubules that stimulates inflammation and tumorigenesis is discovered, suggesting OSM could be a potential target for ccRCC intervention.
      PubDate: 2021-10-01T00:05:31-07:00
      DOI: 10.1158/0008-5472.CAN-21-0345
      Issue No: Vol. 81, No. 19 (2021)
       
  • Epstein-Barr Virus-Encoded Circular RNA CircBART2.2 Promotes Immune Escape
           of Nasopharyngeal Carcinoma by Regulating PD-L1

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      Authors: Junshang Ge; Jie Wang, Fang Xiong, Xianjie Jiang, Kunjie Zhu, Yian Wang, Yongzhen Mo, Zhaojian Gong, Shanshan Zhang, Yi He, Xiayu Li, Lei Shi, Can Guo, Fuyan Wang, Ming Zhou, Bo Xiang, Yong Li, Guiyuan Li, Wei Xiong, Zhaoyang Zeng
      Pages: 5074 - 5088
      Abstract: Epstein–Barr virus (EBV) infection is an established cause of nasopharyngeal carcinoma (NPC) and is involved in a variety of malignant phenotypes, including tumor immune escape. EBV can encode a variety of circular RNAs (circRNA), however, little is known regarding the biological functions of these circRNAs in NPC. In this study, EBV-encoded circBART2.2 was found to be highly expressed in NPC where it upregulated PD-L1 expression and inhibited T-cell function in vitro and in vivo. circBART2.2 promoted transcription of PD-L1 by binding the helicase domain of RIG-I and activating transcription factors IRF3 and NF-κB, resulting in tumor immune escape. These results elucidate the biological function of circBART2.2, explain a novel mechanism of immune escape caused by EBV infection, and provide a new immunotherapy target for treating NPC.Significance:This work demonstrates that circBART2.2 binding to RIG-I is essential for the regulation of PD-L1 and subsequent immune escape in nasopharyngeal carcinoma.
      PubDate: 2021-10-01T00:05:31-07:00
      DOI: 10.1158/0008-5472.CAN-20-4321
      Issue No: Vol. 81, No. 19 (2021)
       
  • TET2 and DNMT3A Mutations Exert Divergent Effects on DNA Repair and
           Sensitivity of Leukemia Cells to PARP Inhibitors

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      Authors: Silvia Maifrede; Bac Viet Le, Margaret Nieborowska-Skorska, Konstantin Golovine, Katherine Sullivan-Reed, Wangisa M.B. Dunuwille, Joseph Nacson, Michael Hulse, Kelsey Keith, Jozef Madzo, Lisa Beatrice Caruso, Zachary Gazze, Zhaorui Lian, Antonella Padella, Kumaraswamy N. Chitrala, Boris A. Bartholdy, Ksenia Matlawska-Wasowska, Daniela Di Marcantonio, Giorgia Simonetti, Georg Greiner, Stephen M. Sykes, Peter Valent, Elisabeth M. Paietta, Martin S. Tallman, Hugo F. Fernandez, Mark R. Litzow, Mark D. Minden, Jian Huang, Giovanni Martinelli, George S. Vassiliou, Italo Tempera, Katarzyna Piwocka, Neil Johnson, Grant A. Challen, Tomasz Skorski
      Pages: 5089 - 5101
      Abstract: Somatic variants in TET2 and DNMT3A are founding mutations in hematological malignancies that affect the epigenetic regulation of DNA methylation. Mutations in both genes often co-occur with activating mutations in genes encoding oncogenic tyrosine kinases such as FLT3ITD, BCR-ABL1, JAK2V617F, and MPLW515L, or with mutations affecting related signaling pathways such as NRASG12D and CALRdel52. Here, we show that TET2 and DNMT3A mutations exert divergent roles in regulating DNA repair activities in leukemia cells expressing these oncogenes. Malignant TET2-deficient cells displayed downregulation of BRCA1 and LIG4, resulting in reduced activity of BRCA1/2-mediated homologous recombination (HR) and DNA-PK–mediated non-homologous end-joining (D-NHEJ), respectively. TET2-deficient cells relied on PARP1-mediated alternative NHEJ (Alt-NHEJ) for protection from the toxic effects of spontaneous and drug-induced DNA double-strand breaks. Conversely, DNMT3A-deficient cells favored HR/D-NHEJ owing to downregulation of PARP1 and reduction of Alt-NHEJ. Consequently, malignant TET2-deficient cells were sensitive to PARP inhibitor (PARPi) treatment in vitro and in vivo, whereas DNMT3A-deficient cells were resistant. Disruption of TET2 dioxygenase activity or TET2—Wilms' tumor 1 (WT1)–binding ability was responsible for DNA repair defects and sensitivity to PARPi associated with TET2 deficiency. Moreover, mutation or deletion of WT1 mimicked the effect of TET2 mutation on DSB repair activity and sensitivity to PARPi. Collectively, these findings reveal that TET2 and WT1 mutations may serve as biomarkers of synthetic lethality triggered by PARPi, which should be explored therapeutically.Significance:TET2 and DNMT3A mutations affect distinct DNA repair mechanisms and govern the differential sensitivities of oncogenic tyrosine kinase–positive malignant hematopoietic cells to PARP inhibitors.
      PubDate: 2021-10-01T00:05:31-07:00
      DOI: 10.1158/0008-5472.CAN-20-3761
      Issue No: Vol. 81, No. 19 (2021)
       
  • Targeting Notch Inhibitors to the Myeloma Bone Marrow Niche Decreases
           Tumor Growth and Bone Destruction without Gut Toxicity

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      Authors: Hayley M. Sabol; Adam J. Ferrari, Manish Adhikari, Tania Amorim, Kevin McAndrews, Judith Anderson, Michele Vigolo, Raȷwinder Lehal, Meloney Cregor, Sharmin Khan, Pedro L. Cuevas, Jill A. Helms, Noriyoshi Kurihara, Venkat Srinivasan, Frank H. Ebetino, Robert K. Boeckman, Jr, G. David Roodman, Teresita Bellido, Jesus Delgado–Calle
      Pages: 5102 - 5114
      Abstract: Systemic inhibition of Notch with γ-secretase inhibitors (GSI) decreases multiple myeloma tumor growth, but the clinical use of GSI is limited due to its severe gastrointestinal toxicity. In this study, we generated a GSI Notch inhibitor specifically directed to the bone (BT-GSI). BT-GSI administration decreased Notch target gene expression in the bone marrow, but it did not alter Notch signaling in intestinal tissue or induce gut toxicity. In mice with established human or murine multiple myeloma, treatment with BT-GSI decreased tumor burden and prevented the progression of multiple myeloma-induced osteolytic disease by inhibiting bone resorption more effectively than unconjugated GSI at equimolar doses. These findings show that BT-GSI has dual anti-myeloma and anti-resorptive properties, supporting the therapeutic approach of bone-targeted Notch inhibition for the treatment of multiple myeloma and associated bone disease.Significance:Development of a bone-targeted Notch inhibitor reduces multiple myeloma growth and mitigates cancer-induced bone destruction without inducing the gastrointestinal toxicity typically associated with inhibition of Notch.
      PubDate: 2021-10-01T00:05:31-07:00
      DOI: 10.1158/0008-5472.CAN-21-0524
      Issue No: Vol. 81, No. 19 (2021)
       
  • Predicting Molecular Phenotypes from Histopathology Images: A
           Transcriptome-Wide Expression-Morphology Analysis in Breast Cancer

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      Authors: Yinxi Wang; Kimmo Kartasalo, Philippe Weitz, Balazs Acs, Masi Valkonen, Christer Larsson, Pekka Ruusuvuori, Johan Hartman, Mattias Rantalainen
      Pages: 5115 - 5126
      Abstract: Molecular profiling is central in cancer precision medicine but remains costly and is based on tumor average profiles. Morphologic patterns observable in histopathology sections from tumors are determined by the underlying molecular phenotype and therefore have the potential to be exploited for prediction of molecular phenotypes. We report here the first transcriptome-wide expression–morphology (EMO) analysis in breast cancer, where individual deep convolutional neural networks were optimized and validated for prediction of mRNA expression in 17,695 genes from hematoxylin and eosin–stained whole slide images. Predicted expressions in 9,334 (52.75%) genes were significantly associated with RNA sequencing estimates. We also demonstrated successful prediction of an mRNA-based proliferation score with established clinical value. The results were validated in independent internal and external test datasets. Predicted spatial intratumor variabilities in expression were validated through spatial transcriptomics profiling. These results suggest that EMO provides a cost-efficient and scalable approach to predict both tumor average and intratumor spatial expression from histopathology images.Significance:Transcriptome-wide expression morphology deep learning analysis enables prediction of mRNA expression and proliferation markers from routine histopathology whole slide images in breast cancer.
      PubDate: 2021-10-01T00:05:31-07:00
      DOI: 10.1158/0008-5472.CAN-21-0482
      Issue No: Vol. 81, No. 19 (2021)
       
  • Correction: YAP Suppresses Lung Squamous Cell Carcinoma Progression via
           Deregulation of the DNp63-GPX2 Axis and ROS Accumulation

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      Authors: Hsinyi Huang; Wenjing Zhang, Yafang Pan, Yijun Gao, Lei Deng, Fuming Li, Fei Li, Xueyan Ma, Shenda Hou, Jing Xu, Peixue Li, Xiaoxun Li, Guohong Hu, Cheng Li, Haiquan Chen, Lei Zhang, Hongbin Ji
      Pages: 5127 - 5127
      PubDate: 2021-10-01T00:05:31-07:00
      DOI: 10.1158/0008-5472.CAN-21-2379
      Issue No: Vol. 81, No. 19 (2021)
       
 
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