MicroRNA-374a activates Wnt/β-catenin signaling to promote breast cancer metastasis

• Text
• PDF

Abstract

Tumor metastasis involves a series of biological steps during which the tumor cells acquire the ability to invade surrounding tissues and survive outside the original tumor site. During the early stages, the cancer cells undergo an epithelial-mesenchymal transition (EMT). Wnt/β-catenin signaling is known to drive EMT and metastasis. Here we report that Wnt/β-catenin signaling is hyperactivated in metastatic breast cancer cells that express microRNA 374a (miR-374a). In breast cancer cell lines, ectopic overexpression of miR-374a promoted EMT and metastasis both in vitro and in vivo. Furthermore, miR-374a directly targeted and suppressed multiple negative regulators of the Wnt/β-catenin signaling cascade, including WIF1, PTEN, and WNT5A. Notably, miR-374a was markedly upregulated in primary tumor samples from patients with distant metastases and was associated with poor metastasis-free survival. These results demonstrate that miR-374a maintains constitutively activated Wnt/β-catenin signaling and may represent a therapeutic target for early metastatic breast cancer.

Authors

Junchao Cai, Hongyu Guan, Lishan Fang, Yi Yang, Xun Zhu, Jie Yuan, Jueheng Wu, Mengfeng Li

KDM2B promotes pancreatic cancer via Polycomb-dependent and -independent transcriptional programs

• Text
• PDF

Abstract

Epigenetic mechanisms mediate heritable control of cell identity in normal cells and cancer. We sought to identify epigenetic regulators driving the pathogenesis of pancreatic ductal adenocarcinoma (PDAC), one of the most lethal human cancers. We found that KDM2B (also known as Ndy1, FBXL10, and JHDM1B), an H3K36 histone demethylase implicated in bypass of cellular senescence and somatic cell reprogramming, is markedly overexpressed in human PDAC, with levels increasing with disease grade and stage, and highest expression in metastases. KDM2B silencing abrogated tumorigenicity of PDAC cell lines exhibiting loss of epithelial differentiation, whereas KDM2B overexpression cooperated with Kras^G12D to promote PDAC formation in mouse models. Gain- and loss-of-function experiments coupled to genome-wide gene expression and ChIP studies revealed that KDM2B drives tumorigenicity through 2 different transcriptional mechanisms. KDM2B repressed developmental genes through cobinding with Polycomb group (PcG) proteins at transcriptional start sites, whereas it activated a module of metabolic genes, including mediators of protein synthesis and mitochondrial function, cobound by the MYC oncogene and the histone demethylase KDM5A. These results defined epigenetic programs through which KDM2B subverts cellular differentiation and drives the pathogenesis of an aggressive subset of PDAC.

Authors

Alexandros Tzatsos, Polina Paskaleva, Francesco Ferrari, Vikram Deshpande, Svetlana Stoykova, Gianmarco Contino, Kwok-Kin Wong, Fei Lan, Patrick Trojer, Peter J. Park, Nabeel Bardeesy

Loss of SPARC in bladder cancer enhances carcinogenesis and progression

• Text
• PDF

Abstract

Secreted protein acidic and rich in cysteine (SPARC) has been implicated in multiple aspects of human cancer. However, its role in bladder carcinogenesis and metastasis are unclear,with some studies suggesting it may be a promoter and others arguing the opposite. Using a chemical carcinogenesis model in Sparc-deficient mice and their wild-type littermates, we found that loss of SPARC accelerated the development of urothelial preneoplasia (atypia and dysplasia), neoplasia, and metastasis and was associated with decreased survival. SPARC reduced carcinogen-induced inflammation and accumulation of reactive oxygen species as well as urothelial cell proliferation. Loss of SPARC was associated with an inflammatory phenotype of tumor-associated macrophages and fibroblasts, with concomitant increased activation of urothelial and stromal NF-κB and AP1 in vivo and in vitro. Syngeneic spontaneous and experimental metastasis models revealed that tumor- and stroma-derived SPARC reduced tumor growth and metastasis through inhibition of cancer-associated inflammation and lung colonization. In human bladder tumor tissues, the frequency and intensity of SPARC expression were inversely correlated with disease-specific survival. These results indicate that SPARC is produced by benign and malignant compartments of bladder carcinomas where it functions to suppress bladder carcinogenesis, progression, and metastasis.

Authors

Neveen Said, Henry F. Frierson, Marta Sanchez-Carbayo, Rolf A. Brekken, Dan Theodorescu

Hepatitis B virus X protein represses miRNA-148a to enhance tumorigenesis

• Text
• PDF

Abstract

MicroRNAs (miRNAs) have been shown to be dysregulated in virus-related cancers; however, miRNA regulation of virus-related cancer development and progression remains poorly understood. Here, we report that miR-148a is repressed by hepatitis B virus (HBV) X protein (HBx) to promote cancer growth and metastasis in a mouse model of hepatocellular carcinoma (HCC). Hematopoietic pre–B cell leukemia transcription factor–interacting protein (HPIP) is an important regulator of cancer cell growth. We used miRNA target prediction programs to identify miR-148a as a regulator of HPIP. Expression of miR-148a in hepatoma cells reduced HPIP expression, leading to repression of AKT and ERK and subsequent inhibition of mTOR through the AKT/ERK/FOXO4/ATF5 pathway. HBx has been shown to play a critical role in the molecular pathogenesis of HBV-related HCC. We found that HBx suppressed p53-mediated activation of miR-148a. Moreover, expression of miR-148a was downregulated in patients with HBV-related liver cancer and negatively correlated with HPIP, which was upregulated in patients with liver cancer. In cultured cells and a mouse xenograft model, miR-148a reduced the growth, epithelial-to-mesenchymal transition, invasion, and metastasis of HBx-expressing hepatocarcinoma cells through inhibition of HPIP-mediated mTOR signaling. Thus, miR-148a activation or HPIP inhibition may be a useful strategy for cancer treatment.

Authors

Xiaojie Xu, Zhongyi Fan, Lei Kang, Juqiang Han, Chengying Jiang, Xiaofei Zheng, Ziman Zhu, Huabo Jiao, Jing Lin, Kai Jiang, Lihua Ding, Hao Zhang, Long Cheng, Hanjiang Fu, Yi Song, Ying Jiang, Jiahong Liu, Rongfu Wang, Nan Du, Qinong Ye

mTORC1 inhibition restricts inflammation-associated gastrointestinal tumorigenesis in mice

• Text
• PDF

Abstract

Gastrointestinal cancers are frequently associated with chronic inflammation and excessive secretion of IL-6 family cytokines, which promote tumorigenesis through persistent activation of the GP130/JAK/STAT3 pathway. Although tumor progression can be prevented by genetic ablation of Stat3 in mice, this transcription factor remains a challenging therapeutic target with a paucity of clinically approved inhibitors. Here, we uncovered parallel and excessive activation of mTOR complex 1 (mTORC1) alongside STAT3 in human intestinal-type gastric cancers (IGCs). Furthermore, in a preclinical mouse model of IGC, GP130 ligand administration simultaneously activated mTORC1/S6 kinase and STAT3 signaling. We therefore investigated whether mTORC1 activation was required for inflammation-associated gastrointestinal tumorigenesis. Strikingly, the mTORC1-specific inhibitor RAD001 potently suppressed initiation and progression of both murine IGC and colitis-associated colon cancer. The therapeutic effect of RAD001 was associated with reduced tumor vascularization and cell proliferation but occurred independently of STAT3 activity. We analyzed the mechanism of GP130-mediated mTORC1 activation in cells and mice and revealed a requirement for JAK and PI3K activity but not for GP130 tyrosine phosphorylation or STAT3. Our results suggest that GP130-dependent activation of the druggable PI3K/mTORC1 pathway is required for inflammation-associated gastrointestinal tumorigenesis. These findings advocate clinical application of PI3K/mTORC1 inhibitors for the treatment of corresponding human malignancies.

Authors

Stefan Thiem, Thomas P. Pierce, Michelle Palmieri, Tracy L. Putoczki, Michael Buchert, Adele Preaudet, Ryan O. Farid, Chris Love, Bruno Catimel, Zhengdeng Lei, Steve Rozen, Veena Gopalakrishnan, Fred Schaper, Michael Hallek, Alex Boussioutas, Patrick Tan, Andrew Jarnicki, Matthias Ernst

EWS/ATF1 expression induces sarcomas from neural crest–derived cells in mice

• Text
• PDF

Abstract

Clear cell sarcoma (CCS) is an aggressive soft tissue malignant tumor characterized by a unique t(12;22) translocation that leads to the expression of a chimeric EWS/ATF1 fusion gene. However, little is known about the mechanisms underlying the involvement of EWS/ATF1 in CCS development. In addition, the cellular origins of CCS have not been determined. Here, we generated EWS/ATF1-inducible mice and examined the effects of EWS/ATF1 expression in adult somatic cells. We found that forced expression of EWS/ATF1 resulted in the development of EWS/ATF1-dependent sarcomas in mice. The histology of EWS/ATF1-induced sarcomas resembled that of CCS, and EWS/ATF1-induced tumor cells expressed CCS markers, including S100, SOX10, and MITF. Lineage-tracing experiments indicated that neural crest–derived cells were subject to EWS/ATF1-driven transformation. EWS/ATF1 directly induced Fos in an ERK-independent manner. Treatment of human and EWS/ATF1-induced CCS tumor cells with FOS-targeted siRNA attenuated proliferation. These findings demonstrated that FOS mediates the growth of EWS/ATF1-associated sarcomas and suggest that FOS is a potential therapeutic target in human CCS.

Authors

Kazunari Yamada, Takatoshi Ohno, Hitomi Aoki, Katsunori Semi, Akira Watanabe, Hiroshi Moritake, Shunichi Shiozawa, Takahiro Kunisada, Yukiko Kobayashi, Junya Toguchida, Katsuji Shimizu, Akira Hara, Yasuhiro Yamada

NOD2-mediated dysbiosis predisposes mice to transmissible colitis and colorectal cancer

• Text
• PDF

Abstract

Instability in the composition of gut bacterial communities (dysbiosis) has been linked to common human intestinal disorders, such as Crohn’s disease and colorectal cancer. Here, we show that dysbiosis caused by Nod2 deficiency gives rise to a reversible, communicable risk of colitis and colitis-associated carcinogenesis in mice. Loss of either Nod2 or RIP2 resulted in a proinflammatory microenvironment that enhanced epithelial dysplasia following chemically induced injury. The condition could be improved by treatment with antibiotics or an anti–interleukin-6 receptor–neutralizing antibody. Genotype-dependent disease risk was communicable via maternally transmitted microbiota in both Nod2-deficient and WT hosts. Furthermore, reciprocal microbiota transplantation reduced disease risk in Nod2-deficient mice and led to long-term changes in intestinal microbial communities. Conversely, disease risk was enhanced in WT hosts that were recolonized with dysbiotic fecal microbiota from Nod2-deficient mice. Thus, we demonstrated that licensing of dysbiotic microbiota is a critical component of disease risk. Our results demonstrate that NOD2 has an unexpected role in shaping a protective assembly of gut bacterial communities and suggest that manipulation of dysbiosis is a potential therapeutic approach in the treatment of human intestinal disorders.

Authors

Aurélie Couturier-Maillard, Thomas Secher, Ateequr Rehman, Sylvain Normand, Adèle De Arcangelis, Robert Haesler, Ludovic Huot, Teddy Grandjean, Aude Bressenot, Anne Delanoye-Crespin, Olivier Gaillot, Stefan Schreiber, Yves Lemoine, Bernhard Ryffel, David Hot, Gabriel Nùñez, Grace Chen, Philip Rosenstiel, Mathias Chamaillard

Convergence of oncogenic and hormone receptor pathways promotes metastatic phenotypes

• Text
• PDF

Abstract

Cyclin D1b is a splice variant of the cell cycle regulator cyclin D1 and is known to harbor divergent and highly oncogenic functions in human cancer. While cyclin D1b is induced during disease progression in many cancer types, the mechanisms underlying cyclin D1b function remain poorly understood. Herein, cell and human tumor xenograft models of prostate cancer were utilized to resolve the downstream pathways that are required for the protumorigenic functions of cyclin D1b. Specifically, cyclin D1b was found to modulate the expression of a large transcriptional network that cooperates with androgen receptor (AR) signaling to enhance tumor cell growth and invasive potential. Notably, cyclin D1b promoted AR-dependent activation of genes associated with metastatic phenotypes. Further exploration determined that transcriptional induction of SNAI2 (Slug) was essential for cyclin D1b–mediated proliferative and invasive properties, implicating Slug as a critical driver of disease progression. Importantly, cyclin D1b expression highly correlated with that of Slug in clinical samples of advanced disease. In vivo analyses provided strong evidence that Slug enhances both tumor growth and metastatic phenotypes. Collectively, these findings reveal the underpinning mechanisms behind the protumorigenic functions of cyclin D1b and demonstrate that the convergence of the cyclin D1b/AR and Slug pathways results in the activation of processes critical for the promotion of lethal tumor phenotypes.

Authors

Michael A. Augello, Craig J. Burd, Ruth Birbe, Christopher McNair, Adam Ertel, Michael S. Magee, Daniel E. Frigo, Kari Wilder-Romans, Mark Shilkrut, Sumin Han, Danielle L. Jernigan, Jeffry L. Dean, Alessandro Fatatis, Donald P. McDonnell, Tapio Visakorpi, Felix Y. Feng, Karen E. Knudsen

Prognostically relevant gene signatures of high-grade serous ovarian carcinoma

• Text
• PDF

Abstract

Because of the high risk of recurrence in high-grade serous ovarian carcinoma (HGS-OvCa), the development of outcome predictors could be valuable for patient stratification. Using the catalog of The Cancer Genome Atlas (TCGA), we developed subtype and survival gene expression signatures, which, when combined, provide a prognostic model of HGS-OvCa classification, named “Classification of Ovarian Cancer” (CLOVAR). We validated CLOVAR on an independent dataset consisting of 879 HGS-OvCa expression profiles. The worst outcome group, accounting for 23% of all cases, was associated with a median survival of 23 months and a platinum resistance rate of 63%, versus a median survival of 46 months and platinum resistance rate of 23% in other cases. Associating the outcome prediction model with BRCA1/BRCA2 mutation status, residual disease after surgery, and disease stage further optimized outcome classification. Ovarian cancer is a disease in urgent need of more effective therapies. The spectrum of outcomes observed here and their association with CLOVAR signatures suggests variations in underlying tumor biology. Prospective validation of the CLOVAR model in the context of additional prognostic variables may provide a rationale for optimal combination of patient and treatment regimens.

Authors

Roel G.W. Verhaak, Pablo Tamayo, Ji-Yeon Yang, Diana Hubbard, Hailei Zhang, Chad J. Creighton, Sian Fereday, Michael Lawrence, Scott L. Carter, Craig H. Mermel, Aleksandar D. Kostic, Dariush Etemadmoghadam, Gordon Saksena, Kristian Cibulskis, Sekhar Duraisamy, Keren Levanon, Carrie Sougnez, Aviad Tsherniak, Sebastian Gomez, Robert Onofrio, Stacey Gabriel, Lynda Chin, Nianxiang Zhang, Paul T. Spellman, Yiqun Zhang, Rehan Akbani, Katherine A. Hoadley, Ari Kahn, Martin Köbel, David Huntsman, Robert A. Soslow, Anna Defazio, Michael J. Birrer, Joe W. Gray, John N. Weinstein, David D. Bowtell, Ronny Drapkin, Jill P. Mesirov, Gad Getz, Douglas A. Levine, Matthew Meyerson

TGF-β upregulates miR-181a expression to promote breast cancer metastasis

• Text
• PDF

Abstract

Late-stage breast cancer metastasis is driven by dysregulated TGF-β signaling, but the underlying molecular mechanisms have not been fully elucidated. We attempted to recapitulate tumor and metastatic microenvironments via the use of biomechanically compliant or rigid 3D organotypic cultures and combined them with global microRNA (miR) profiling analyses to identify miRs that were upregulated in metastatic breast cancer cells by TGF-β. Here we establish miR-181a as a TGF-β–regulated “metastamir” that enhanced the metastatic potential of breast cancers by promoting epithelial-mesenchymal transition, migratory, and invasive phenotypes. Mechanistically, inactivation of miR-181a elevated the expression of the proapoptotic molecule Bim, which sensitized metastatic cells to anoikis. Along these lines, miR-181a expression was essential in driving pulmonary micrometastatic outgrowth and enhancing the lethality of late-stage mammary tumors in mice. Finally, miR-181a expression was dramatically and selectively upregulated in metastatic breast tumors, particularly triple-negative breast cancers, and was highly predictive for decreased overall survival in human breast cancer patients. Collectively, our findings strongly implicate miR-181a as a predictive biomarker for breast cancer metastasis and patient survival, and consequently, as a potential therapeutic target in metastatic breast cancer.

Authors

Molly A. Taylor, Khalid Sossey-Alaoui, Cheryl L. Thompson, David Danielpour, William P. Schiemann