Menée sur plusieurs centaines de lignées cellulaires cancéreuses humaines et à l'aide de données issues de la base "Catalog of Somatic Mutations in Cancer", cette étude dresse un catalogue des mutations du gène TP53 et, pour chaque mutation, estime l'avantage évolutif conféré par l'atténuation de l'activité de ce gène suppresseur de tumeurs

Mutational processes shape the landscape of TP53 mutations in human cancer

Giacomelli, Andrew O. ; Yang, Xiaoping ; Lintner, Robert E. ; McFarland, James M. ; Duby, Marc ; Kim, Jaegil ; Howard, Thomas P. ; Takeda, David Y. ; Ly, Seav Huong ; Kim, Eejung ; Gannon, Hugh S. ; Hurhula, Brian ; Sharpe, Ted ; Goodale, Amy ; Fritchman, Briana ; Steelman, Scott ; Vazquez, Francisca ; Tsherniak, Aviad ; Aguirre, Andrew J. ; Doench, John G. ; Piccioni, Federica ; Roberts, Charles W. M. ; Meyerson, Matthew ; Getz, Gad ; Johannessen, Cory M. ; Root, David E. ; Hahn, William C.

Unlike most tumor suppressor genes, the most common genetic alterations in tumor protein p53 (TP53) are missense mutations1,2. Mutant p53 protein is often abundantly expressed in cancers and specific allelic variants exhibit dominant-negative or gain-of-function activities in experimental models3–8. To gain a systematic view of p53 function, we interrogated loss-of-function screens conducted in hundreds of human cancer cell lines and performed TP53 saturation mutagenesis screens in an isogenic [...]

A partir d'échantillons tumoraux prélevés sur 15 patients africains et européens atteints d'un cancer de la prostate à haut risque, cette étude de séquençage du génome entier évalue le taux de mutations oncogéniques en fonction de l'origine ethnique des patients

Whole Genome Sequencing Reveals Elevated Tumor Mutational Burden and Initiating Driver Mutations in African Men with Treatment-Naive, High-Risk Prostate Cancer

Jaratlerdsiri, Weerachai ; Chan, Eva K. F. ; Gong, Tingting ; Petersen, Desiree C. ; Kalsbeek, Anton M. F. ; Venter, Philip A. ; Stricker, Phillip D. ; Bornman, M. S. Riana ; Hayes, Vanessa M.

African American men are more likely than any other racial group to die from prostate cancer. The contribution of acquired genomic variation to this racial disparity is largely unknown, as genomic from Africa is lacking. Here we performed the first tumor-normal paired deep whole-genome sequencing for Africa. A direct study-matched comparison between African- and European-derived, treatment-naïve, high-risk prostate tumors for 15 cases allowed for further comparative analyses of existing data. [...]

Menée à l'aide de modèles murins présentant la mutation V600E du gène BRAF durant le développement précoce du cerveau, cette étude met en évidence des mécanismes permettant de rendre compte de l'association entre tumeurs cérébrales de l'enfant et crises d'épilepsie

BRAF somatic mutation contributes to intrinsic epileptogenicity in pediatric brain tumors

Koh, Hyun Yong ; Kim, Se Hoon ; Jang, Jaeson ; Kim, Hyungguk ; Han, Sungwook ; Lim, Jae Seok ; Son, Geurim ; Choi, Junjeong ; Park, Byung Ouk ; Do Heo, Won ; Han, Jinju ; Lee, Hyunjoo Jenny ; Lee, Daeyoup ; Kang, Hoon-Chul ; Shong, Minho ; Paik, Se-Bum ; Kim, Dong Seok ; Lee, Jeong Ho

Pediatric brain tumors are highly associated with epileptic seizures1. However, their epileptogenic mechanisms remain unclear. Here, we show that the oncogenic BRAF somatic mutation p.Val600Glu (V600E) in developing neurons underlies intrinsic epileptogenicity in ganglioglioma, one of the leading causes of intractable epilepsy2. To do so, we developed a mouse model harboring the BRAFV600E somatic mutation during early brain development to reflect the most frequent mutation, as well as the [...]

A partir d'échantillons tumoraux prélevés sur 13 patients atteints d'un lymphome folliculaire et 13 patients atteints d'un lymphome diffus à grandes cellules B, cette étude met en évidence des mécanismes par lesquels la sous-expression du micro-ARN miR-150 favorise la transformation d'un lymphome indolent en un lymphome de haut grade

miR-150 downregulation contributes to the high-grade transformation of follicular lymphoma by upregulating FOXP1 levels

Musilova, Katerina ; Devan, Jan ; Cerna, Katerina ; Seda, Vaclav ; Pavlasova, Gabriela ; Sharma, Sonali ; Oppelt, Jan ; Pytlik, Robert ; Prochazka, Vit ; Prouzova, Zuzana ; Trbusek, Martin ; Zlamalikova, Lenka ; Liskova, Kvetoslava ; Kruzova, Lenka ; Jarosova, Marie ; Mareckova, Andrea ; Kornauth, Christoph ; Simonitsch-Klupp, Ingrid ; Schiefer, Ana-Iris ; Merkel, Olaf ; Mocikova, Heidi ; Burda, Pavel ; Machova Polakova, Katerina ; Kren, Leos ; Mayer, Jiri ; Zent, Clive S. ; Trneny, Marek ; Evans, Andrew G. ; Janikova, Andrea ; Mraz, Marek

miR-150 is down-modulated with transformation of FL leading to upregulation of FOXP1 protein. Upregulation of MYC protein is responsible for the repression of miR-150 in transformed FL. Follicular lymphoma (FL) is a common indolent B-cell malignancy with a variable clinical course. An unfavorable event in its course is histological transformation to a high-grade lymphoma, typically diffuse large B-cell lymphoma (DLBCL). Recent studies show that genetic aberrations of MYC or its overexpression [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels, en régulant la voie de signalisation MEK/FRA1/SOX10, l'enzyme UBE2N favorise la croissance d'un mélanome

UBE2N promotes melanoma growth via MEK/FRA1/SOX10 signaling

Dikshit, Anushka ; Jin, Yingai J. ; Degan, Simone ; Hwang, Jihwan ; Foster, Matthew W. ; Li, Chuan-Yuan ; Zhang, Jennifer Y.

UBE2N is a K63-specific ubiquitin conjugase linked to various immune disorders and cancer. Here we demonstrate that UBE2N and its partners UBE2V1 and UBE2V2 are highly expressed in malignant melanoma. Silencing of UBE2N and its partners significantly decreased melanoma cell proliferation and subcutaneous tumor growth. This was accompanied by increased expression of E-cadherin, p16, and MC1R and decreased expression of melanoma malignancy markers including SOX10, Nestin, and ABCB5. Mass [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels, en induisant la traduction d'un ensemble d'ARNs messagers oncogéniques, la protéine METTL3 favorise la prolifération de cellules cancéreuses du poumon

mRNA circularization by METTL3–eIF3h enhances translation and promotes oncogenesis

Choe, Junho ; Lin, Shuibin ; Zhang, Wencai ; Liu, Qi ; Wang, Longfei ; Ramirez-Moya, Julia ; Du, Peng ; Kim, Wantae ; Tang, Shaojun ; Sliz, Piotr ; Santisteban, Pilar ; George, Rani E. ; Richards, William G. ; Wong, Kwok-Kin ; Locker, Nicolas ; Slack, Frank J. ; Gregory, Richard I.

N6-methyladenosine (m6A) modification of mRNA is emerging as an important regulator of gene expression that affects different developmental and biological processes, and altered m6A homeostasis is linked to cancer1–5. m6A modification is catalysed by METTL3 and enriched in the 3′ untranslated region of a large subset of mRNAs at sites close to the stop codon5. METTL3 can promote translation but the mechanism and relevance of this process remain unknown1. Here we show that METTL3 enhances [...]

Menée in vitro et in vivo, cette étude identifie une population de cellules hybrides qui, issues d'une fusion entre cellules cancéreuses et leucocytes, contribuent à l'hétérogénéité d'une tumeur et au processus métastatique

Cell fusion potentiates tumor heterogeneity and reveals circulating hybrid cells that correlate with stage and survival

Gast, Charles E. ; Silk, Alain D. ; Zarour, Luai ; Riegler, Lara ; Burkhart, Joshua G. ; Gustafson, Kyle T. ; Parappilly, Michael S. ; Roh-Johnson, Minna ; Goodman, James R. ; Olson, Brennan ; Schmidt, Mark ; Swain, John R. ; Davies, Paige S. ; Shasthri, Vidya ; Iizuka, Shinji ; Flynn, Patrick ; Watson, Spencer ; Korkola, James ; Courtneidge, Sara A. ; Fischer, Jared M. ; Jaboin, Jerry ; Billingsley, Kevin G. ; Lopez, Charles D. ; Burchard, Julja ; Gray, Joe ; Coussens, Lisa M. ; Sheppard, Brett C. ; Wong, Melissa H.

High lethality rates associated with metastatic cancer highlight an urgent medical need for improved understanding of biologic mechanisms driving metastatic spread and identification of biomarkers predicting late-stage progression. Numerous neoplastic cell intrinsic and extrinsic mechanisms fuel tumor progression; however, mechanisms driving heterogeneity of neoplastic cells in solid tumors remain obscure. Increased mutational rates of neoplastic cells in stressed environments are implicated [...]

Menée in vitro, in vivo et à l'aide d'échantillons de tumeurs primitives et de métastases prélevés sur des patients atteints d'un cancer (tête et cou, côlon, estomac, sein), cette étude met en évidence des mécanismes par lesquels l'interleukine 3, sécrétée par des macrophages associés aux tumeurs, favorise le processus métastatique

Macrophage-secreted interleukin-35 regulates cancer cell plasticity to facilitate metastatic colonization

Lee, Chih-Chan ; Lin, Jiunn-Chang ; Hwang, Wei-Lun ; Kuo, Ying-Ju ; Chen, Hung-Kai ; Tai, Shyh-Kuan ; Lin, Chun-Chi ; Yang, Muh-Hwa

A favorable interplay between cancer cells and the tumor microenvironment (TME) facilitates the outgrowth of metastatic tumors. Because of the distinct initiating processes between primary and metastatic tumors, we investigate the differences in tumor-associated macrophages (TAMs) from primary and metastatic cancers. Here we show that dual expression of M1 and M2 markers is noted in TAMs from primary tumors, whereas predominant expression of M2 markers is shown in metastatic TAMs. At metastatic [...]

Cet article passe en revue les travaux récents sur le rôle joué par des cellules souches dans la croissance d'une tumeur, dans sa progression et dans la résistance thérapeutique

Stem cell fate in cancer growth, progression and therapy resistance

Lytle, Nikki K. ; Barber, Alison G. ; Reya, Tannishtha

Although we have come a long way in our understanding of the signals that drive cancer growth, and how these signals can be targeted, effective control of this disease remains a key scientific and medical challenge. The therapy resistance and relapse that are commonly seen are driven in large part by the inherent heterogeneity within cancers that allows drugs to effectively eliminate some, but not all, malignant cells. Here, we focus on the fundamental drivers of this heterogeneity by examining [...]

Menée à l'aide de plusieurs modèles murins de cancer du poumon à petites cellules, cette étude met en évidence l'importance du type cellulaire à l'origine d'une tumeur pour déterminer son potentiel métastatique

Intertumoral Heterogeneity in SCLC Is Influenced by the Cell Type of Origin

Yang, Dian ; Denny, Sarah K. ; Greenside, Peyton G. ; Chaikovsky, Andrea C. ; Brady, Jennifer J. ; Ouadah, Youcef ; Granja, Jeffrey M. ; Jahchan, Nadine S. ; Lim, Jing Shan ; Kwok, Shirley ; Kong, Christina S. ; Berghoff, Anna S. ; Schmitt, Anna ; Reinhardt, H. Christian ; Park, Kwon-Sik ; Preusser, Matthias ; Kundaje, Anshul ; Greenleaf, William J. ; Sage, Julien ; Winslow, Monte M.

The extent to which early events shape tumor evolution is largely uncharacterized, even though a better understanding of these early events may help identify key vulnerabilities in advanced tumors. Here, using genetically defined mouse models of small cell lung cancer (SCLC), we uncovered distinct metastatic programs attributable to the cell type of origin. In one model, tumors gain metastatic ability through amplification of the transcription factor NFIB and a widespread increase in chromatin [...]

A partir d'échantillons tumoraux prélevés sur 266 patients atteints d'un cancer de la vessie, puis menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels, en modulant le micro-environnement tumoral, le long ARN non codant LNMAT1 favorise la formation de métastases dans les ganglions lymphatiques

LNMAT1 promotes lymphatic metastasis of bladder cancer via CCL2 dependent macrophage recruitment

Chen, Changhao ; He, Wang ; Huang, Jian ; Wang, Bo ; Li, Hui ; Cai, Qingqing ; Su, Feng ; Bi, Junming ; Liu, Hongwei ; Zhang, Bin ; Jiang, Ning ; Zhong, Guangzheng ; Zhao, Yue ; Dong, Wen ; Lin, Tianxin

Tumor-associated macrophages (TAMs) are the most abundant inflammatory infiltrates in the tumor microenvironment and contribute to lymph node (LN) metastasis. However, the precise mechanisms of TAMs-induced LN metastasis remain largely unknown. Herein, we identify a long noncoding RNA, termed Lymph Node Metastasis Associated Transcript 1 (LNMAT1), which is upregulated in LN-positive bladder cancer and associated with LN metastasis and prognosis. Through gain and loss of function approaches, we [...]

Cet article présente un nouvel outil en ligne, d'accès libre et gratuit, permettant de visualiser des données d'expression de gènes d'intérêt à partir de plusieurs bases de données bien annotées

CANCERTOOL: a visualization and representation interface to exploit cancer datasets

Cortazar, Ana R. ; Torrano, Verónica ; Martín-Martín, Natalia ; Caro-Maldonado, Alfredo ; Camacho, Laura ; Hermanova, Ivana ; Guruceaga, Elizabeth ; Lorenzo-Martín, Luis F. ; Caloto, Ruben ; Gomis, Roger R. ; Apaolaza, Iñigo ; Quesada, Victor ; Trka, Jan ; Gomez-Muñoz, Antonio ; Vicent, Silvestre ; Bustelo, Xose R. ; Planes, Francisco J. ; Aransay, Ana M. ; Carracedo, Arkaitz

With the advent of OMICs technologies, both individual research groups and consortia have spear-headed the characterization of human samples of multiple pathophysiological origins, resulting in thousands of archived genomes and transcriptomes. Although a variety of web tools are now available to extract information from OMICs data, their utility has been limited by the capacity of non-bioinformatician researchers to exploit the information. To address this problem, we have developed CANCERTOOL, [...]

Cette étude passe en revue les travaux récents sur les mécanismes par lesquels les anomalies d'expression des enzymes du cycle de l'urée favorisent la prolifération des cellules tumorales

Rewiring urea cycle metabolism in cancer to support anabolism

Keshet, Rom ; Szlosarek, Peter ; Carracedo, Arkaitz ; Erez, Ayelet

Cancer cells reprogramme metabolism to maximize the use of nitrogen and carbon for the anabolic synthesis of macromolecules that are required during tumour proliferation and growth. To achieve this aim, one strategy is to reduce catabolism and nitrogen disposal. The urea cycle (UC) in the liver is the main metabolic pathway to convert excess nitrogen into disposable urea. Outside the liver, UC enzymes are differentially expressed, enabling the use of nitrogen for the synthesis of UC [...]

Menée sur des cultures cellulaires de rétine humaine n'exprimant pas le gène RB1, cette étude suggère que les modèles murins de rétinoblastome ne reproduisent pas l'évolution d'une lésion précurseur dans un cône en une tumeur maligne chez l'humain

Developmental stage-specific proliferation and retinoblastoma genesis in RB-deficient human but not mouse cone precursors

Singh, Hardeep P. ; Wang, Sijia ; Stachelek, Kevin ; Lee, Sunhye ; Reid, Mark W. ; Thornton, Matthew E. ; Craft, Cheryl Mae ; Grubbs, Brendan H. ; Cobrinik, David

Retinoblastoma is a childhood tumor that forms in response to mutations in the RB1 gene and loss of functional RB protein. Prior studies suggested that retinoblastomas arise from cone photoreceptor precursors, whereas mouse models yield tumors deriving from other retinal cell types and lacking human retinoblastoma features. We show that in cultured human retinae, retinoblastomas initiate from RB-depleted cone precursors that are in a specific maturation state and form premalignant retinomas [...]