Menée à l'aide de lignées cellulaires de cancer du côlon, cette étude analyse le mécanisme moléculaire par lequel le récepteur aux estrogènes ER bêta favorise la suppression tumorale

Genome-Wide Estrogen Receptor β Chromatin Binding in Human Colon Cancer Cells Reveals its Tumor Suppressor Activity

Indukuri, Rajitha ; Jafferali, Mohammed Hakim ; Song, Dandan ; Damdimopoulos, Anastasius ; Hases, Linnea ; Zhao, Chunyan ; Archer, Amena ; Williams, Cecilia

Colorectal cancer (CRC) is the third leading cause of cancer death in the western world. In women, menopausal hormone therapy has been shown to reduce CRC incidence by 20%. Studies demonstrate that estrogen activating estrogen receptor beta (ER

Menée à l'aide de lignées cellulaires et de modèles murins de carcinome épidermoïde de l'oesophage, cette étude met en évidence un mécanisme par lequel les protéines TP53 mutées, en induisant l'expression de la survivine, favorisent le développement de métastases pulmonaires

Mutant p53 regulates Survivin to foster lung metastasis

Tang, Qiaosi ; Efe, Gizem ; Chiarella, Anna M. ; Leung, Jessica ; Chen, Maoting ; Yamazoe, Taiji ; Su, Zhenyi ; Pitarresi, Jason R. ; Li, Jinyang ; Islam, Mirazul ; Karakasheva, Tatiana ; Klein-Szanto, Andres J. ; Pan, Samuel ; Hu, Jianhua ; Natsugoe, Shoji ; Gu, Wei ; Stanger, Ben Z. ; Wong, Kwok-K ; Diehl, J. Alan ; Bass, Adam J. ; Nakagawa, Hiroshi ; Murphy, Maureen E. ; Rustgi, Anil K.

Esophageal squamous cell carcinoma (ESCC) is one of the most lethal cancers worldwide and evolves often to lung metastasis. P53R175H (homologous to Trp53R172H in mice) is a common hot spot mutation. How metastasis is regulated by p53R175H in ESCC remains to be investigated. To investigate p53R175H-mediated molecular mechanisms, we used a carcinogen-induced approach in Trp53R172H/− mice to model ESCC. In the primary Trp53R172H/− tumor cell lines, we depleted Trp53R172H (shTrp53) and observed a [...]

Cet article analyse les interactions entre les cellules tumorales et les différents microenvironnements tissulaires de la moelle osseuse afin de comprendre le mécanisme de développement des métastases osseuses

Bone marrow niches in the regulation of bone metastasis

Chen, Fenfang ; Han, Yujiao ; Kang, Yibin

The bone marrow has been widely recognised to host a unique microenvironment that facilitates tumour colonisation. Bone metastasis frequently occurs in the late stages of malignant diseases such as breast, prostate and lung cancers. The biology of bone metastasis is determined by tumour-cell-intrinsic traits as well as their interaction with the microenvironment. The bone marrow is a dynamic organ in which various stages of haematopoiesis, osteogenesis, osteolysis and different kinds of immune [...]

Menée in vitro et à l'aide de modèles murins de cancer du côlon associé à une colite ou spontané, cette étude met en évidence un mécanisme par lequel l'activation de la voie de signalisation du récepteur GPR35 des macrophages favorise l'angiogenèse dans le microenvironnement tumoral

Activation of the GPR35 pathway drives angiogenesis in the tumour microenvironment

Pagano, Ester ; Elias, Joshua E. ; Schneditz, Georg ; Saveljeva, Svetlana ; Holland, Lorraine M. ; Borrelli, Francesca ; Karlsen, Tom H. ; Kaser, Arthur ; Kaneider, Nicole

Objective : Primary sclerosing cholangitis (PSC) is in 70% of cases associated with inflammatory bowel disease. The hypermorphic T108M variant of the orphan G protein-coupled receptor GPR35 increases risk for PSC and ulcerative colitis (UC), conditions strongly predisposing for inflammation-associated liver and colon cancer. Lack of GPR35 reduces tumour numbers in mouse models of spontaneous and colitis associated cancer. The tumour microenvironment substantially determines tumour growth, and [...]

Menée à l'aide de modèles murins de cancer mammaire, cette étude démontre que la tumeur peut à distance, via des facteurs qu'elle sécrète, altérer la qualité et l'architecture des régions osseuses sujettes aux métastases

Breast cancer–secreted factors perturb murine bone growth in regions prone to metastasis

Chiou, Aaron E. ; Liu, Chuang ; Moreno-Jiménez, Inés ; Tang, Tengteng ; Wagermaier, Wolfgang ; Dean, Mason N. ; Fischbach, Claudia ; Fratzl, Peter

Breast cancer frequently metastasizes to bone, causing osteolytic lesions. However, how factors secreted by primary tumors affect the bone microenvironment before the osteolytic phase of metastatic tumor growth remains unclear. Understanding these changes is critical as they may regulate metastatic dissemination and progression. To mimic premetastatic bone adaptation, immunocompromised mice were injected with MDA-MB-231–conditioned medium [tumor-conditioned media (TCM)]. Subsequently, the bones [...]

Menée à partir du séquençage de l'ADN de 16 178 cellules issues de 8 tumeurs mammaires de type triple négatif et de 4 lignées cellulaires, cette étude met en évidence le maintien d'une diversité sous-clonale de cellules cancéreuses durant la croissance tumorale

Breast tumours maintain a reservoir of subclonal diversity during expansion

Minussi, Darlan C. ; Nicholson, Michael D. ; Ye, Hanghui ; Davis, Alexander ; Wang, Kaile ; Baker, Toby ; Tarabichi, Maxime ; Sei, Emi ; Du, Haowei ; Rabbani, Mashiat ; Peng, Cheng ; Hu, Min ; Bai, Shanshan ; Lin, Yu-wei ; Schalck, Aislyn ; Multani, Asha ; Ma, Jin ; McDonald, Thomas O. ; Casasent, Anna ; Barrera, Angelica ; Chen, Hui ; Lim, Bora ; Arun, Banu ; Meric-Bernstam, Funda ; Van Loo, Peter ; Michor, Franziska ; Navin, Nicholas E.

Our knowledge of copy number evolution during the expansion of primary breast tumours is limited1,2. Here, to investigate this process, we developed a single-cell, single-molecule DNA-sequencing method and performed copy number analysis of 16,178 single cells from 8 human triple-negative breast cancers and 4 cell lines. The results show that breast tumours and cell lines comprise a large milieu of subclones (7–22) that are organized into a few (3–5) major superclones. Evolutionary analysis [...]

Menée à partir de l'analyse de données génomiques et transcriptomiques portant sur 82 lignées cellulaires de cancers pédiatriques, cette étude identifie les caractéristiques et dépendances génétiques de 13 types tumoraux

A first-generation pediatric cancer dependency map

Dharia, Neekesh V. ; Kugener, Guillaume ; Guenther, Lillian M. ; Malone, Clare F. ; Durbin, Adam D. ; Hong, Andrew L. ; Howard, Thomas P. ; Bandopadhayay, Pratiti ; Wechsler, Caroline S. ; Fung, Iris ; Warren, Allison C. ; Dempster, Joshua M. ; Krill-Burger, John M. ; Paolella, Brenton R. ; Moh, Phoebe ; Jha, Nishant ; Tang, Andrew ; Montgomery, Philip ; Boehm, Jesse S. ; Hahn, William C. ; Roberts, Charles W. M. ; McFarland, James M. ; Tsherniak, Aviad ; Golub, Todd R. ; Vazquez, Francisca ; Stegmaier, Kimberly

Exciting therapeutic targets are emerging from CRISPR-based screens of high mutational-burden adult cancers. A key question, however, is whether functional genomic approaches will yield new targets in pediatric cancers, known for remarkably few mutations, which often encode proteins considered challenging drug targets. To address this, we created a first-generation pediatric cancer dependency map representing 13 pediatric solid and brain tumor types. Eighty-two pediatric cancer cell lines were [...]

Menée in vitro à l'aide de la spectrométrie de masse et de la cryo-microscopie électronique, cette étude analyse les interactions moléculaires entre le domaine catalytique du facteur d'échange nucléotidique "Son of Sevenless" et les formes mutées oncogènes de la protéine KRAS

Molecular assemblies of the catalytic domain of SOS with KRas and oncogenic mutants

Moghadamchargari, Zahra ; Shirzadeh, Mehdi ; Liu, Chang ; Schrecke, Samantha ; Packianathan, Charles ; Russell, David H. ; Zhao, Minglei ; Laganowsky, Arthur

Disrupting the interaction between Ras and SOS has emerged as an attractive therapeutic strategy. Here, we characterized the assembly of the catalytic domain of SOS (SOScat) with oncogenic KRas mutants using native mass spectrometry. By resolving distinct molecular species, we show KRas mutants engage SOScat differently and the G13D KRas mutant robustly engages SOScat. A structure of KRasG13D in complex with SOScat shows repositioning of switch I and II regions within KRasG13D. Moreover, potent [...]

Menée à l'aide d'un modèle murin de mélanome, cette étude met en évidence un mécanisme par lequel l'interleukine IL-7 prévient l'inhibition par l'adénosine de l'activité antitumorale des lymphocytes T CD8+

Interleukin-7 protects CD8+ T cells from adenosine-mediated immunosuppression

Koyas, Altay ; Tucer, Suat ; Kayhan, Merve ; Savas, Ali Can ; Akdemir, Imran ; Cekic, Caglar

Within the tumor microenvironment, the nucleoside adenosine accumulates and acts through its cell surface receptors to inhibit the activity of antitumor CD8+ T cells. To alleviate this immunosuppression, therapeutics that target either adenosine production or adenosine receptor signaling are being developed. Koyas et al. showed in mice that the actions of adenosine on tumor-infiltrating CD8+ T cells depended on the milieu within the tumor. In particular, signaling by the cytokine interleukin-7 [...]

Menée à l'aide notamment de lignées cellulaires de cancer du sein et d'une xénogreffe sur un modèle murin, cette étude met en évidence un mécanisme par lequel l'enzyme GREB1 stabilise les récepteurs ER alpha des cellules cancéreuses et démontre une association entre l'expression de cette enzyme et la réponse tumorale au tamoxifène

GREB1: An evolutionarily conserved protein with a glycosyltransferase domain links ERalpha glycosylation and stability to cancer

Shin, Eun Myoung ; Huynh, Vinh Thang ; Neja, Sultan Abda ; Liu, Chia Yi ; Raju, Anandhkumar ; Tan, Kelly ; Tan, Nguan Soon ; Gunaratne, Jayantha ; Bi, Xuezhi ; Iyer, Lakshminarayan M. ; Aravind, L. ; Tergaonkar, Vinay

What covalent modifications control the temporal ubiquitination of ERα and hence the duration of its transcriptional activity remain poorly understood. We show that GREB1, an ERα-inducible enzyme, catalyzes O-GlcNAcylation of ERα at residues T553/S554, which stabilizes ERα protein by inhibiting association with the ubiquitin ligase ZNF598. Loss of GREB1-mediated glycosylation of ERα results in reduced cellular ERα levels and insensitivity to estrogen. Higher GREB1 expression in ERα+ve breast [...]