A partir d'échantillons tumoraux prélevés sur 54 patients atteints d'un cancer pédiatrique, cette étude met en évidence quatre trajectoires évolutionnistes possibles pour le développement de populations clonales distinctes à l'intérieur d'une tumeur primitive

Four evolutionary trajectories underlie genetic intratumoral variation in childhood cancer

Karlsson, Jenny ; Valind, Anders ; Holmquist Mengelbier, Linda ; Bredin, Sofia ; Cornmark, Louise ; Jansson, Caroline ; Wali, Amina ; Staaf, Johan ; Viklund, Björn ; Øra, Ingrid ; Börjesson, Anna ; Backman, Torbjörn ; Braekeveldt, Noémie ; Sandstedt, Bengt ; Pal, Niklas ; Isaksson, Anders ; Lackner, Barbara Gürtl ; Jonson, Tord ; Bexell, Daniel ; Gisselsson, David

A major challenge to personalized oncology is that driver mutations vary among cancer cells inhabiting the same tumor. Whether this reflects principally disparate patterns of Darwinian evolution in different tumor regions has remained unexplored. We mapped the prevalence of genetically distinct clones over 250 regions in 54 childhood cancers. This showed that primary tumors can simultaneously follow up to four evolutionary trajectories over different anatomic areas. The most common pattern [...]

A partir d'échantillons sanguins prélevés sur 1 021 patients adultes atteints d'une leucémie myéloïde aiguë, cette étude évalue la fréquence des mutations du gène NF1 et analyse l'association entre ces mutations et le taux de rémission complète ou la survie globale

NF1 mutations are recurrent in adult acute myeloid leukemia and confer poor outcome

Eisfeld, Ann-Kathrin ; Kohlschmidt, Jessica ; Mrózek, Krzysztof ; Mims, Alice ; Walker, Christopher J. ; Blachly, James S. ; Nicolet, Deedra ; Orwick, Shelley ; Maharry, Sophia E. ; Carroll, Andrew J. ; Powell, Bayard L. ; Kolitz, Jonathan E. ; Wang, Eunice S. ; Stone, Richard M. ; de la Chapelle, Albert ; Byrd, John C. ; Bloomfield, Clara D.

Targeted mutation assessment of 81 genes in 1021 adults with de novo acute myeloid leukemia (AML) identified recurrent mutations in the neurofibromin 1 (NF1) gene in 52 (5.1%) patients, including 36 (5.2%) younger and 16 (4.8%) older patients, which suggests NF1 belongs to the 20 most frequently mutated genes in adult AML. NF1 mutations were found throughout the gene, and comprised missense, frameshift, and nonsense mutations. One mutation hotspot, at amino acid threonine 676 (Thr676), was [...]

Menée à l'aide de modèles murins de cholangiocarcinome intra-hépatique, cette étude met en évidence le rôle joué par des mutations des gènes Kras et TP53 dans le développement d'une tumeur

Kras and Tp53 mutations cause cholangiocyte- and hepatocyte-derived cholangiocarcinoma

Hill, Margaret A. ; Alexander, William B. ; Guo, Bing ; Kato, Yasutaka ; Patra, Krushna Chandra ; Dell, Michael R. ; McCall, Matthew N. ; Whitney-Miller, Christa L. ; Bardeesy, Nabeel ; Hezel, Aram F.

Intrahepatic cholangiocarcinoma (iCCA) is a primary liver cancer epidemiologically linked with liver injury which has poorly understood incipient stages and lacks early diagnostics and effective therapies. While iCCA is conventionally thought to arise from the biliary tract, studies have suggested that both hepatocytes and biliary cells (cholangiocytes) may give rise to iCCA. Consistent with the plasticity of these cell lineages, primary liver carcinomas exhibit a phenotypic range from [...]

Menée sur des lignées cellulaires et à l'aide de modèles murins, cette étude met en évidence des mécanismes par lesquels, lorsqu'elle est exprimée dans les fibroblastes associés au cancer du micro-environnement tumoral, la protéine p53 est susceptible de favoriser la progression de la tumeur

Altered p53 functionality in cancer-associated fibroblasts contributes to their cancer-supporting features

Arandkar, Sharathchandra ; Furth, Noa ; Elisha, Yair ; Nataraj, Nishanth Belugali ; van der Kuip, Heiko ; Yarden, Yosef ; Aulitzky, Walter ; Ulitsky, Igor ; Geiger, Benjamin ; Oren, Moshe

p53 research has primarily addressed its cell-autonomous tumor-suppressive features. Yet, recent evidence suggests that, in normal tissues, p53 can also exert cell nonautonomous tumor suppressor activities. Cancer-associated fibroblasts (CAFs) enhance the malignant features of adjacent cancer cells. Surprisingly, we found that the conversion of normal fibroblasts to CAFs entails nonmutational alteration of their p53, such that it now becomes cancer supportive rather than cancer inhibitory. This [...]

Menée sur des lignées cellulaires et à l'aide de modèles murins, cette étude met en évidence des mécanismes par lesquels, en cas de perte d'expression du gène p53, plusieurs gènes impliqués dans les processus de réparation de l'ADN sont susceptibles d'inhiber le développement d'un lymphome

DNA repair processes are critical mediators of p53-dependent tumor suppression

Janic, Ana ; Valente, Liz J. ; Wakefield, Matthew J. ; Di Stefano, Leon ; Milla, Liz ; Wilcox, Stephen ; Yang, Haoyu ; Tai, Lin ; Vandenberg, Cassandra J. ; Kueh, Andrew J. ; Mizutani, Shinsuke ; Brennan, Margs S. ; Schenk, Robyn L. ; Lindqvist, Lisa M. ; Papenfuss, Anthony T. ; O’Connor, Liam ; Strasser, Andreas ; Herold, Marco J.

It has long been assumed that p53 suppresses tumor development through induction of apoptosis, possibly with contributions by cell cycle arrest and cell senescence. However, combined deficiency in these three processes does not result in spontaneous tumor formation as observed upon loss of p53, suggesting the existence of additional mechanisms that are critical mediators of p53-dependent tumor suppression function. To define such mechanisms, we performed in vivo shRNA screens targeting [...]

A partir d'échantillons tumoraux prélevés sur 1 273 patients atteints d'un myélome multiple récemment diagnostiqué, cette étude identifie notamment 63 nouveaux gènes dont des mutations sont associées au développement de la maladie

Identification of novel mutational drivers reveals oncogene dependencies in multiple myeloma

Walker, Brian A. ; Mavrommatis, Konstantinos ; Wardell, Christopher P. ; Ashby, T. Cody ; Bauer, Michael ; Davies, Faith E. ; Rosenthal, Adam ; Wang, Hongwei ; Qu, Pingping ; Hoering, Antje ; Samur, Mehmet ; Towfic, Fadi ; Ortiz, Maria ; Flynt, Erin ; Yu, Zhinuan ; Yang, Zhihong ; Rozelle, Dan ; Obenauer, John ; Trotter, Matthew ; Auclair, Daniel ; Keats, Jonathan ; Bolli, Niccolo ; Fulciniti, Mariateresa ; Szalat, Raphael ; Moreau, Philippe ; Durie, Brian ; Stewart, A. Keith ; Goldschmidt, Hartmut ; Raab, Marc S. ; Einsele, Hermann ; Sonneveld, Pieter ; San Miguel, Jesús ; Lonial, Sagar ; Jackson, Graham H. ; Anderson, Kenneth C. ; Avet-Loiseau, Hervé ; Munshi, Nikhil ; Thakurta, Anjan ; Morgan, Gareth J.

Using the largest set of newly diagnosed myeloma patients we have identified 63 mutated driver genes.We identify oncogenic dependencies, particularly relating to primary translocations, indicating a non-random accumulation of genetic hits. Understanding the profile of oncogene and tumor suppressor gene mutations with their interactions and impact on the prognosis of multiple myeloma (MM) can improve the definition of disease subsets and identify pathways important in disease pathobiology. Using [...]

Menée sur des lignées cellulaires de cancer de la prostate et à l'aide de xénogrefffes sur des modèles murins, cette étude met en évidence des mécanismes par lesquels la protéine EMP1 favorise le processus métastatique

Epithelial membrane protein 1 promotes tumor metastasis by enhancing cell migration via copine-III and Rac1

Ahmat Amin, Mohammad Khusni B. ; Shimizu, Akio ; Zankov, Dimitar P. ; Sato, Akira ; Kurita, Souichi ; Ito, Masami ; Maeda, Toshinaga ; Yoshida, Tetsuya ; Sakaue, Tomohisa ; Higashiyama, Shigeki ; Kawauchi, Akihiro ; Ogita, Hisakazu

Tumor metastasis is the most common cause of cancer death. Elucidation of the mechanism of tumor metastasis is therefore important in the development of novel, effective anti-cancer therapies to reduce cancer mortality. Interaction between cancer cells and surrounding stromal cells in the tumor microenvironment is a key factor in tumor metastasis. Using a co-culture assay system with human prostate cancer LNCaP cells and primary human prostate stromal cells, we identified epithelial membrane [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels le récepteur des acides lysophosphatiques LPA1 augmente la capacité des cellules cancéreuses à produire des invadopodes dans un environnement hypoxique et, en lien avec le récepteur EGFR, favorise le processus métastatique

The Hypoxic Tumor Microenvironment Promotes Invadopodia Formation and Metastasis through LPA1 Receptor and EGFR Cooperation

Harper, Kelly ; R.Lavoie, Roxane ; Charbonneau, Martine ; Brochu-Gaudreau, Karine ; Dubois, Claire M.

Hypoxia, a common feature of solid tumors, has been critically involved in cell invasion and metastasis but the underlying mechanisms remain poorly understood. Previously, it has been observed that the lysophosphatidic acid receptor 4 (LPA4) signaling axis mediates production of the degradative subcellular structures invadopodia, which are known to be required for metastasis. Here, it is demonstrated that LPA1 (LPAR1) is a common and major receptor used for hypoxia-induced invadopodia [...]

Menée in vitro et in vivo sur des modèles de cancer métastatique, cette étude met en évidence des mécanismes par lesquels la protéine ZIP14 favorise le développement d'une cachexie

Metastatic cancers promote cachexia through ZIP14 upregulation in skeletal muscle

Wang, Gang ; Biswas, Anup K. ; Ma, Wanchao ; Kandpal, Manoj ; Coker, Courtney ; Grandgenett, Paul M. ; Hollingsworth, Michael A. ; Jain, Rinku ; Tanji, Kurenai ; Lόpez-Pintado, Sara ; Borczuk, Alain ; Hebert, Doreen ; Jenkitkasemwong, Supak ; Hojyo, Shintaro ; Davuluri, Ramana V. ; Knutson, Mitchell D. ; Fukada, Toshiyuki ; Acharyya, Swarnali

Patients with metastatic cancer experience a severe loss of skeletal muscle mass and function known as cachexia. Cachexia is associated with poor prognosis and accelerated death in patients with cancer, yet its underlying mechanisms remain poorly understood. Here, we identify the metal-ion transporter ZRT- and IRT-like protein 14 (ZIP14) as a critical mediator of cancer-induced cachexia. ZIP14 is upregulated in cachectic muscles of mice and in patients with metastatic cancer and can be induced [...]

Menée in vitro et in vivo sur des modèles de cancer du pancréas, cette étude met en évidence des mécanismes par lesquels, en produisant des exosomes riches en micro-ARN miR-301a-3p au sein d'un micro-environnement hypoxique, les cellules cancéreuses favorisent le processus métastatique

Hypoxic tumor-derived exosomal miR-301a mediates M2 macrophage polarization via PTEN/PI3Kgamma to promote pancreatic cancer metastasis

Wang, Xiaofeng ; Luo, Guangtao ; Zhang, Kundong ; Cao, Jun ; Huang, Chen ; Jiang, Tao ; Liu, Bingya ; Su, Liping ; Qiu, Zhengjun

Exosomes are emerging as important mediators of the crosstalk between tumor cells and the microenvironment. However, the mechanisms by which exosomes modulate tumor development under hypoxia in pancreatic cancer (PC) remain largely unknown. Here we found that hypoxic exosomes derived from PC cells activate macrophages to the M2 phenotype in a HIF-1a or HIF-2a-dependent manner, which then facilitates the migration, invasion, and EMT of PC cells. Given that exosomes have been shown to transport [...]

A partir d'échantillons de tumeur primitive et de ganglions lymphatiques prélevés sur 11 patientes atteintes d'un cancer du sein de stade précoce, puis à l'aide d'une analyse de l'ADN tumoral circulant, cette étude met en évidence l'évolution des populations clonales au cours de la dissémination des cellules cancéreuses

The spatio-temporal evolution of lymph node spread in early breast cancer

Barry, Peter ; Vatsiou, Alexandra ; Spiteri, Inmaculada ; Nichol, Daniel ; Cresswell, George D. ; Acar, Ahmet ; Trahearn, Nicholas A. ; Hrebien, Sarah ; Garcia-Murillas, Isaac ; Chkhaidze, Kate ; Ermini, Luca ; Said Huntingford, Ian ; Cottom, Hannah ; Zabaglo, Lila ; Koelble, Konrad ; Khalique, Saira ; Rusby, Jennifer E. ; Muscara, Francesca ; Dowsett, Mitch ; Maley, Carlo C. ; Natrajan, Rachael ; Yuan, Yinyin ; Schiavon, Gaia ; Turner, Nicholas C. ; Sottoriva, Andrea

Purpose: The most significant prognostic factor in early breast cancer is lymph node involvement. This stage between localised and systemic disease is key to understanding breast cancer progression, however our knowledge of the evolution of lymph node malignant invasion remains limited, as most currently available data derive from primary tumours. Experimental design: In 11 treatment-naïve node positive early breast cancer patients without clinical evidence of distant metastasis, we [...]