一周快讯：本周表观文献精选（2018.2.10）

Adipocyte-induced CD36 expression drives ovarian cancer progression and metastasis

Andras Ladanyi, Abir Mukherjee, Hilary A. Kenny, Alyssa Johnson, Anirban K. Mitra, Sinju Sundaresan, Kristin M. Nieman, Gloria Pascual, Salvador Aznar Benitah ， Anthony Montag, S. Diane Yamada, Nada A. Abumrad & Ernst Lengyel

原文链接：

http://www.nature.com/articles/s41388-017-0093-z

原文摘要：Ovarian cancer (OvCa) is characterized by widespread and rapid metastasis in the peritoneal cavity. Visceral adipocytes promote this process by providing fatty acids (FAs) for tumour growth. However, the exact mechanism of FA transfer from adipocytes to cancer cells remains unknown. This study shows that OvCa cells co-cultured with primary human omental adipocytes express high levels of the FA receptor, CD36, in the plasma membrane, thereby facilitating exogenous FA uptake. Depriving OvCa cells of adipocyte-derived FAs using CD36 inhibitors and short hairpin RNA knockdown prevented development of the adipocyte-induced malignant phenotype. Specifically, inhibition of CD36 attenuated adipocyte-induced cholesterol and lipid droplet accumulation and reduced intracellular reactive oxygen species (ROS) content. Metabolic analysis suggested that CD36 plays an essential role in the bioenergetic adaptation of OvCa cells in the adipocyte-rich microenvironment and governs their metabolic plasticity. Furthermore, the absence of CD36 affected cellular processes that play a causal role in peritoneal dissemination, including adhesion, invasion, migration and anchorage independent growth. Intraperitoneal injection of CD36-deficient cells or treatment with an anti-CD36 monoclonal antibody reduced tumour burden in mouse xenografts. Moreover, a matched cohort of primary and metastatic human ovarian tumours showed upregulation of CD36 in the metastatic tissues, a finding confirmed in three public gene expression data sets. These results suggest that omental adipocytes reprogram tumour metabolism through the upregulation of CD36 in OvCa cells. Targeting the stromal-tumour metabolic interface via CD36 inhibition may prove to be an effective treatment strategy against OvCa metastasis.

Novel identification of STAT1 as a crucial mediator of ETV6-NTRK3-induced tumorigenesis

Jinah Park, Junil Kim, Bora Park, Kyung-Min Yang, Eun Jin Sun, Cristina E. Tognon, Poul H. Sorensen  & Seong-Jin Kim

原文链接：

http://www.nature.com/articles/s41388-017-0102-2

原文摘要：

Chromosomal rearrangements that facilitate tumor formation and progression through activation of oncogenic tyrosine kinases are frequently observed in cancer. The ETV6-NTRK3 (EN) fusion has been implicated in various cancers, including infantile fibrosarcoma, secretory breast carcinoma, and acute myeloblastic leukemia, and has exhibited in vivo and in vitro transforming ability. In the present study, we analyzed transcriptome alterations using DNA microarray and RNA-Seq in EN-transduced NIH3T3 fibroblasts to identify the mechanisms that are involved in EN-mediated tumorigenesis. Through functional profile assessment of EN-regulated transcriptome alterations, we found that upregulated genes by EN were mainly associated with cell motion, membrane invagination, and cell proliferation, while downregulated genes were involved in cell adhesion, which correlated with the transforming potential and increased proliferation in EN-transduced cells. KEGG pathway analysis identified the JAK-STAT signaling pathway with the highest statistical significance. Moreover, Ingenuity Pathway Analysis and gene regulatory network analysis identified the STAT1 transcription factor and its target genes as top EN-regulated molecules. We further demonstrated that EN enhanced STAT1 phosphorylation but attenuated STAT1 acetylation, eventually inhibiting the interaction between the NF-κB p65 subunit and acetylated STAT1. Consequently, nuclear translocation of NF-κB p65 and subsequent NF-κB activity were increased by EN. Notably, inhibition of STAT1 phosphorylation attenuated tumorigenic ability of EN in vitro and in vivo. Taken together, here we report, for the first time, STAT1 as a significant EN-regulated transcription factor and a crucial mediator of EN-induced tumorigenesis.

Characterizing steroid hormone receptor chromatin binding landscapes in male and female breast cancer

Tesa M. Severson, Yongsoo Kim, Stacey E. P. Joosten, Karianne Schuurman, Petra van der Groep, Cathy B. Moelans, Natalie D. ter Hoeve, Quirine F. Manson, John W. Martens , Carolien H. M. van Deurzen, Ellis Barbe, Ingrid Hedenfalk, Peter Bult, Vincent T. H. B. M. Smit Sabine C. Linn, Paul J. van Diest ³ , Lodewyk Wessels  & Wilbert Zwart

原文链接：

http://www.nature.com/articles/s41467-018-02856-2

原文摘要：Male breast cancer (MBC) is rare and poorly characterized. Like the female counterpart, most MBCs are hormonally driven, but relapse after hormonal treatment is also noted. The pan-hormonal action of steroid hormonal receptors, including estrogen receptor alpha (ERα), androgen receptor (AR), progesterone receptor (PR), and glucocorticoid receptor (GR) in this understudied tumor type remains wholly unexamined. This study reveals genomic cross-talk of steroid hormone receptor action and interplay in human tumors, here in the context of MBC, in relation to the female disease and patient outcome. Here we report the characterization of human breast tumors of both genders for cistromic make-up of hormonal regulation in human tumors, revealing genome-wide chromatin binding landscapes of ERα, AR, PR, GR, FOXA1, and GATA3 and enhancer-enriched histone mark H3K4me1. We integrate these data with transcriptomics to reveal gender-selective and genomic location-specific hormone receptor actions, which associate with survival in MBC patients.

Asparagine bioavailability governs metastasis in a model of breast cancer

Simon R. V. Knott, Elvin Wagenblast，Showkhin Khan, Sun Y. Kim ，Mar Soto, Michel Wagner, Marc-Olivier Turgeon, Lisa Fish, Nicolas Erard1, Annika L. Gable, Ashley R. Maceli, Steffen Dickopf, Evangelia K. Papachristou, Clive S. D’Santos, Lisa A. Carey, John E. Wilkinson J. Chuck Harrell, Charles M. Perou, Hani Goodarzi, George Poulogiannis & Gregory J. Hannon

原文链接：

https://www.nature.com/articles/nature25465

原文摘要：Using a functional model of breast cancer heterogeneity, we previously showed that clonal sub-populations proficient at generating circulating tumour cells were not all equally capable of forming metastases at secondary sites1. A combination of differential expression and focused in vitro and in vivo RNA interference screens revealed candidate drivers of metastasis that discriminated metastatic clones. Among these, asparagine synthetase expression in a patient’s primary tumour was most strongly correlated with later metastatic relapse. Here we show that asparagine bioavailability strongly influences metastatic potential. Limiting asparagine by knockdown of asparagine synthetase, treatment with l-asparaginase, or dietary asparagine restriction reduces metastasis without affecting growth of the primary tumour, whereas increased dietary asparagine or enforced asparagine synthetase expression promotes metastatic progression. Altering asparagine availability in vitro strongly influences invasive potential, which is correlated with an effect on proteins that promote the epithelial-to-mesenchymal transition. This provides at least one potential mechanism for how the bioavailability of a single amino acid could regulate metastatic progression.

Tumour spheres with inverted polarity drive the formation of peritoneal metastases in patients with hypermethylated colorectal carcinomas

Olivier Zajac, Joel Raingeaud, Fotine Libanje, Celine Lefebvre, Dora Sabino, Isabelle Martins, Pétronille Roy, Clara Benatar, Charlotte Canet-Jourdan, Paula Azorin, Mélanie Polrot, Patrick Gonin , Salima Benbarche , Sylvie Souquere, Gerard Pierron, Damien Nowak, Ludovic Bigot,Michel Ducreux, David Malka,Camille Lobry ，Jean-Yves Scoazec, Clarisse Eveno, Marc Pocard, Jean-Luc Perfettini , Dominique Elias, Peggy Dartigues, Diane Goéré & Fanny Jaulin - Show fewer authors

原文链接：

https://www.nature.com/articles/s41556-017-0027-6

原文摘要：Metastases account for 90% of cancer-related deaths; thus, it is vital to understand the biology of tumour dissemination. Here, we collected and monitored >50 patient specimens ex vivo to investigate the cell biology of colorectal cancer (CRC) metastatic spread to the peritoneum. This reveals an unpredicted mode of dissemination. Large clusters of cancer epithelial cells displaying a robust outward apical pole, which we termed tumour spheres with inverted polarity (TSIPs), were observed throughout the process of dissemination. TSIPs form and propagate through the collective apical budding of hypermethylated CRCs downstream of canonical and non-canonical transforming growth factor-β signalling. TSIPs maintain their apical-out topology and use actomyosin contractility to collectively invade three-dimensional extracellular matrices. TSIPs invade paired patient peritoneum explants, initiate metastases in mice xenograft models and correlate with adverse patient prognosis. Thus, despite their epithelial architecture and inverted topology TSIPs seem to drive the metastatic spread of hypermethylated CRCs.

Structural basis for DNMT3A-mediated de novo DNA methylation

Zhi-Min Zhang, Rui Lu, Pengcheng Wang, Yang Yu, Dongliang Chen, Linfeng Gao, Shuo Liu, Debin Ji, Scott B Rothbart, Yinsheng Wang, Gang Greg Wang & Jikui Song

原文链接：

https://www.nature.com/articles/nature25477

原文摘要：DNA methylation by de novo DNA methyltransferases 3A (DNMT3A) and 3B (DNMT3B) at cytosines is essential for genome regulation and development1,2. Dysregulation of this process is implicated in various diseases, notably cancer. However, the mechanisms underlying DNMT3 substrate recognition and enzymatic specificity remain elusive. Here we report a 2.65-ångström crystal structure of the DNMT3A–DNMT3L–DNA complex in which two DNMT3A monomers simultaneously attack two cytosine–phosphate–guanine (CpG) dinucleotides, with the target sites separated by 14 base pairs within the same DNA duplex. The DNMT3A–DNA interaction involves a target recognition domain, a catalytic loop, and DNMT3A homodimeric interface. Arg836 of the target recognition domain makes crucial contacts with CpG, ensuring DNMT3A enzymatic preference towards CpG sites in cells. Haematological cancer-associated somatic mutations of the substrate-binding residues decrease DNMT3A activity, induce CpG hypomethylation, and promote transformation of haematopoietic cells. Together, our study reveals the mechanistic basis for DNMT3A-mediated DNA methylation and establishes its aetiological link to human disease.