Breaking Advances Highlights from Recent Cancer Literature

Cancer Research Breaking Advances Highlights from Recent Cancer Literature

NR2F1 Reprograms Malignant Cells into Dormancy

Sosa and colleagues reveal that the orphan nuclear receptor NR2F1, which is involved in lineage commitment and silenced in human tumors and metastasis, is upregulated in solitary dormant tumor cells in cancer patients and mouse models. Retinoic acid induced NR2F1 expression and disseminated tumor cell (DTC) dormancy via induction of SOX9, RARb, and CDK inhibitors. Further, dormant tumor cells acquired a repressive chromatin state that was NR2F1 dependent. Surprisingly, NR2F1 induced NANOG and SOX2, with SOX2 required for dormancy of bone marrow DTCs. Importantly, transient treatment with the DNA methyltransferase inhibitor 5-azacytidine, followed by all-trans retinoic acid, restored NR2F1 expression and key dormancy hallmarks and induced long-term in vivo quiescence of malignant cells. This study reveals novel mechanisms of dormancy, new markers for dormant DTCs in patients, and a therapeutic strategy to prevent metastasis by inducing dormant residual disease. (Image courtesy of Wikimedia Commons.)

Sosa MS, Parikh F, Gaspar Maia A, Estrada Y, Bosch A, Bragado P, et al. NR2F1 controls tumour cell dormancy via SOX9- and RARb-driven quiescence programmes. Nat Commun 2015;6:6170.

Somatic Mutations within Splicing Motifs in Human Cancers

Chen and colleagues integrated genome and exon level transcriptome data in cerebella and peripheral ganglia from a transgenic mouse model of neuroblastoma, a tumor arising from the peripheral neural crest. In this report they describe splicing quantitative trait loci associated with differential splicing across the genome, identifying genes with previously unknown functions within the splicing pathway and deﬁning de novo intronic splicing motifs that inﬂuence splicing from hundreds of bases away. They extended their studies to human cancer by analyzing whole genome sequencing from glioma and neuroblastoma tumors, identifying novel candidate genes with functional implications in the process, and validating effects on splicing through analysis of paired somatic and tumor RNA-seq data in the glioma cohort. These studies identify intronic splicing motifs that translate into sites for recurrent somatic mutations in human cancers. (Image from cited article courtesy of publisher.)

Chen J, Hackett CS, Zhang S, Song YK, Bell RJ, Molinaro AM, et al. The genetics of splicing in neuroblastoma. Cancer Discovery; Published OnlineFirst January 30, 2015; doi:10.1158/2159-8290.CD-14-0892.

Role of ERK5 in Inﬂammation-Driven Cancer

While several cancers are associated with chronic inflammation, the role of cancer-associated inflammation versus benign chronic inflammation is unknown. Finegan and colleagues show that extracellular-regulated protein kinase 5 (ERK5, MAPK7) regulates expression of inflammatory mediators that trigger recruitment of inflammatory cells capable of supporting skin carcinogenesis. ERK5 maintains vascular integrity during development and angiogenesis. Using transgenic mice, the investigators show that inactivation of ERK5 prevented carcinogen-induced and inflammation-driven tumorigenesis. ERK5 regulated expression of IL1b, which is known to sustain and propagate inflammation. Anti-ERK5 therapy effectively synergized with existing antimitotic therapies. Thus, ERK5 represents a novel therapeutic target for inflammation-driven skin tumorigenesis that might extend to other tumor types as well. (Image from cited article courtesy of publisher.)

Finegan KG, Perez-Madrigal D, Hitchin JR, Davies CC, Jordan AM, Tournier C. ERK5 is a critical mediator of inﬂammation- driven cancer. Cancer Res 2015;75:742–53.

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Aberrant Epithelial Extrusion and Hallmarks of Cancer

Apical epithelial extrusion is regulated by sphingosine 1-phosphate (S1P) and its receptors (SIP2, S1PR2). Gu and colleagues now show that loss of S1P2 signaling leads to early cancer progression, evidenced by multilayering, resistance to anoikis, or death induced by chemotherapeutics, and, dangerously, basal extrusion, which could lead to organ parenchyma invasion observed in invasive tumors and in premalignant lesions thought to be noninvasive. Pancreatic tumors showed

reduced S1P2 signaling; restoration of this pathway abrogated tumor growth. Anoikis resistance is activated by focal adhesion kinase (FAK, PTK2) signaling. FAK inhibitors restored normal extrusion pathways and reduced tumor growth across systems, including a zebraﬁsh model. Importantly, normal tissues were not affected, suggesting that these inhibitors might be selective for cancers with malfunctioning extrusion pathways. These studies offer a new pathway and mechanism enabling epithelial cells to access stromal compartments and the circulatory system. (Image by Larry D. Moore courtesy of Wikimedia Commons.)

Gu Y, Shea J, Slattum G, Firpo MA, Alexander M, Mulvihill SJ, et al. Defective apical extrusion signaling contributes to aggressive tumor hallmarks. Elife 2015 Jan 26;4.

A Conserved Migration Machinery Drives Metastasis

Adaptive mechanisms promoting cell migration and metastatic potential remain unclear. Madsen and colleagues studied components of STRIPAK, a protein complex that regulates the phosphatase PP2A. STRIPAK components FAM40A (STRIP1) and FAM40B (STRIP2) regulated cell contractility, migration, and breast cancer metastasis through MST3/4 (STK24/26) kinases and their downstream substrates. Loss of FAM40A activated MST3/4, inducing cell contractility and migration, and enhanced breast cancer cell dissemination into the lungs. Loss of FAM40B, a competitive inhibitor of FAM40A, had the opposite effect. In line with these data, high MST3 and MST4 expression was correlated with increased aggressiveness in breast cancer. Moreover, cancer-derived dominant negative mutants of FAM40B triggered cell contractility in vitro, suggesting a role in breast cancer progression. As MST kinases and FAM40B are deregulated or mutated in multiple human cancers, these proteins may enable cancer cells to adopt different migratory behaviors and promote neoplastic progression. (Image by Jlosada courtesy of Wikimedia Commons.)

Madsen CD, Hooper S, Tozluoglu M, Bruckbauer A, Fletcher G, Erler JT, et al. STRIPAK components determine mode of cancer cell migration and metastasis. Nat Cell Biol 2015;17:68–80.

Phosphorylation of FADD Promotes KRAS-Induced Lung Cancer

In the cytoplasm, phosphorylation of Fas-associated death domain (FADD) promotes apoptosis. However, nuclear phosphorylated FADD promotes survival and proliferation, and increased levels of phosphorylated FADD in lung cancer patients correlate with poor outcome. In a Kras-driven mouse model of lung cancer, deletion of Fadd suppressed tumor growth and decreased the activation of RAS effector pathways. In mouse embryonic ﬁbroblasts, phosphorylation of FADD by casein kinase1a (CK1a, CSNK1A) was required for Kras-driven mitosis. Phosphorylated FADD

interacted physically with a number of protein kinases pivotal for the G2M transition, interactions that were reduced in response to a small-molecule CK1 inhibitor. In vivo, deletion of Csnk1a reduced FADD phosphorylation and suppressed murine Kras-driven lung cancer. These ﬁndings suggest CK1a as a novel therapeutic target. (Image courtesy of Wikimedia Commons.)

Bowman BM, Sebolt KA, Hoff BA, Boes JL, Daniels DL, Heist KA, et al. Phosphorylation of FADD by the kinase CK1a promotes KRASG12D-induced lung cancer. Sci Signal 2015;8:ra9.

Note: Breaking Advances are written by Cancer Research editors. Readers are encouraged to consult the articles referred to in each item for full details on the ﬁndings described.

906 Cancer Research

Cancer Res 2015;75:905-906.

Updated version Access the most recent version of this article at: http://cancerres.aacrjournals.org/content/75/6/905

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