Cet article passe en revue les travaux récents sur les mécanismes par lesquels certaines mutations affectant l'un des 3 gènes RAS (HRAS, NRAS et KRAS) sont susceptibles de favoriser le développement de cellules tumorales

A model for RAS mutation patterns in cancers: finding the sweet spot

Li, Siqi ; Balmain, Allan ; Counter, Christopher M.

The three RAS genes — HRAS, NRAS and KRAS — are collectively mutated in one-third of human cancers, where they act as prototypic oncogenes. Interestingly, there are rather distinct patterns to RAS mutations; the isoform mutated as well as the position and type of substitution vary between different cancers. As RAS genes are among the earliest, if not the first, genes mutated in a variety of cancers, understanding how these mutation patterns arise could inform on not only how cancer begins but [...]

A partir de données issues du projet "International Cancer Genome Consortium" portant sur 560 échantillons tumoraux prélevés sur des patientes atteintes d'un cancer du sein, cette étude met en évidence une association entre l'activité de liaison du récepteur des estrogènes et une accumulation de mutations somatiques non codantes dans le site de liaison

Recurrent mutations at estrogen receptor binding sites alter chromatin topology and distal gene expression in breast cancer

Yang, Jiekun ; Wei, Xiaolong ; Tufan, Turan ; Kuscu, Cem ; Unlu, Hayrunnisa ; Farooq, Saadia ; Demirtas, Elif ; Paschal, Bryce M. ; Adli, Mazhar

Background : The mutational processes underlying non-coding cancer mutations and their biological significance in tumor evolution are poorly understood. To get better insights into the biological mechanisms of mutational processes in breast cancer, we integrate whole-genome level somatic mutations from breast cancer patients with chromatin states and transcription factor binding events. Results : We discover that a large fraction of non-coding somatic mutations in estrogen receptor [...]

Cet article passe en revue les travaux récents sur les mécanismes par lesquels la signalisation mTOR et le métabolisme des cellules cancéreuses interagissent lors de la tumorigenèse

mTOR signalling and cellular metabolism are mutual determinants in cancer

Mossmann, Dirk ; Park, Sujin ; Hall, Michael N.

Oncogenic signalling and metabolic alterations are interrelated in cancer cells. mTOR, which is frequently activated in cancer, controls cell growth and metabolism. mTOR signalling regulates amino acid, glucose, nucleotide, fatty acid and lipid metabolism. Conversely, metabolic inputs, such as amino acids, activate mTOR. In this Review, we discuss how mTOR signalling rewires cancer cell metabolism and delineate how changes in metabolism, in turn, sustain mTOR signalling and tumorigenicity. [...]

Menée à l'aide de modèles murins, cette étude met en évidence des mécanismes par lesquels, via l'arginine dans la circulation sanguine, l'autophagie favorise la croissance tumorale

Autophagy maintains tumour growth through circulating arginine

Poillet-Perez, Laura ; Xie, Xiaoqi ; Zhan, Le ; Yang, Yang ; Sharp, Daniel W. ; Hu, Zhixian Sherrie ; Su, Xiaoyang ; Maganti, Anurag ; Jiang, Cherry ; Lu, Wenyun ; Zheng, Haiyan ; Bosenberg, Marcus W. ; Mehnert, Janice M. ; Guo, Jessie Yanxiang ; Lattime, Edmund ; Rabinowitz, Joshua D. ; White, Eileen

Autophagy captures intracellular components and delivers them to lysosomes, where they are degraded and recycled to sustain metabolism and to enable survival during starvation. Acute, whole-body deletion of the essential autophagy gene Atg7 in adult mice causes a systemic metabolic defect that manifests as starvation intolerance and gradual loss of white adipose tissue, liver glycogen and muscle mass. Cancer cells also benefit from autophagy. Deletion of essential autophagy genes impairs the [...]

Menée sur des lignées cellulaires de leucémie myéloïde aiguë, cette étude met en évidence des mécanismes par lesquels, en fonction de mutations des gènes codant pour des facteurs de transcription (RUNX1, CEBPalpha), des molécules de signalisation (FTL3-ITD, RAS) et une protéine nucléaire (NPM1), un réseau de signalisation spécifique favorise la prolifération des cellules leucémiques

Subtype-specific regulatory network rewiring in acute myeloid leukemia

Assi, Salam A. ; Imperato, Maria Rosaria ; Coleman, Daniel J. L. ; Pickin, Anna ; Potluri, Sandeep ; Ptasinska, Anetta ; Chin, Paulynn Suyin ; Blair, Helen ; Cauchy, Pierre ; James, Sally R. ; Zacarias-Cabeza, Joaquin ; Gilding, L. Niall ; Beggs, Andrew ; Clokie, Sam ; Loke, Justin C. ; Jenkin, Phil ; Uddin, Ash ; Delwel, Ruud ; Richards, Stephen J. ; Raghavan, Manoj ; Griffiths, Michael J. ; Heidenreich, Olaf ; Cockerill, Peter N. ; Bonifer, Constanze

Acute myeloid leukemia (AML) is a heterogeneous disease caused by a variety of alterations in transcription factors, epigenetic regulators and signaling molecules. To determine how different mutant regulators establish AML subtype–specific transcriptional networks, we performed a comprehensive global analysis of cis-regulatory element activity and interaction, transcription factor occupancy and gene expression patterns in purified leukemic blast cells. Here, we focused on specific subgroups of [...]

Menée à l'aide de modèles murins et de xénogreffes dérivées de patients, cette étude met en évidence des mécanismes par lesquels la perte d'expression du gène JARID2 induit la transformation d'une néoplasie myéloproliférative en une leucémie myéloïde aiguë

JARID2 Functions as a Tumor Suppressor in Myeloid Neoplasms by Repressing Self-Renewal in Hematopoietic Progenitor Cells

Celik, Hamza ; Koh, Won Kyun ; Kramer, Ashley C. ; Ostrander, Elizabeth L. ; Mallaney, Cates ; Fisher, Daniel A. C. ; Xiang, Jingyu ; Wilson, William C. ; Martens, Andrew ; Kothari, Alok ; Fishberger, Gregory ; Tycksen, Eric ; Karpova, Darja ; Duncavage, Eric J. ; Lee, Youngsook ; Oh, Stephen T. ; Challen, Grant A.

How specific genetic lesions contribute to transformation of non-malignant myeloproliferative neoplasms (MPNs) and myelodysplastic syndromes (MDSs) to secondary acute myeloid leukemia (sAML) are poorly understood. JARID2 is lost by chromosomal deletions in a proportion of MPN/MDS cases that progress to sAML. In this study, genetic mouse models and patient-derived xenografts demonstrated that JARID2 acts as a tumor suppressor in chronic myeloid disorders. Genetic deletion of Jarid2 either [...]

Menée à l'aide de xénogreffes dérivées de patients atteints d'un mélanome, d'un cancer du côlon ou du pancréas, cette étude met en évidence des mécanismes par lesquels, en régulant l'expression du gène Sox2, la protéine CDK1 favorise le développement d'un mélanome

CDK1 Interacts with Sox2 and Promotes Tumor Initiation in Human Melanoma

Ravindran Menon, Dinoop ; Luo, Yuchun ; Arcaroli, John J. ; Liu, Sucai ; KrishnanKutty, Lekha Nair ; Osborne, Douglas G. ; Li, Yang ; Samson, Jenny Mae ; Bagby, Stacey ; Tan, Aik-Choon ; Robinson, William A. ; Messersmith, Wells A. ; Fujita, Mayumi

Cancers are composed of heterogeneous subpopulations with various tumor-initiating capacities, yet key stem cell genes associated with enhanced tumor-initiating capacities and their regulatory mechanisms remain elusive. Here, we analyzed patient-derived xenografts from melanoma, colon, and pancreatic cancer tissues and identified enrichment of tumor-initiating cells in MHC class I-hi cells, where CDK1, a master regulator of the cell cycle, was upregulated. Overexpression of CDK1, but not its [...]

Menée in vitro et in vivo sur des modèles d'adénocarcinome canalaire du pancréas, cette étude met en évidence des mécanismes par lesquels le facteur de transcription TP63 favorise le développement du sous-type épidermoïde de ces tumeurs

TP63-Mediated Enhancer Reprogramming Drives the Squamous Subtype of Pancreatic Ductal Adenocarcinoma

Somerville, Tim D. D. ; Xu, Yali ; Miyabayashi, Koji ; Tiriac, Herve ; Cleary, Cristian R. ; Maia-Silva, Diogo ; Milazzo, Joseph P. ; Tuveson, David A. ; Vakoc, Christopher R.

The aberrant expression of squamous lineage markers in pancreatic ductal adenocarcinoma (PDA) has been correlated with poor clinical outcomes. However, the functional role of this putative transdifferentiation event in PDA pathogenesis remains unclear. Here, we show that expression of the transcription factor TP63 (?Np63) is sufficient to install and sustain the enhancer landscape and transcriptional signature of the squamous lineage in human PDA cells. We also demonstrate that TP63-driven [...]

A partir de données issues du projet "The Cancer Genome Atlas" portant sur 515 échantillons tumoraux prélevés sur des patients atteints d'un adénocarcinome pulmonaire, puis menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels, lorsque le gène suppresseur de tumeurs LKB1 est inactivé, la protéine INSL4 favorise la prolifération des cellules tumorales

Role of INSL4 Signaling in Sustaining the Growth and Viability of LKB1-Inactivated Lung Cancer

Yang, Rongqiang ; Li, Steven W. ; Chen, Zirong ; Zhou, Xin ; Ni, Wei ; Fu, Dongtao A. ; Lu, Jianrong ; Kaye, Frederic J. ; Wu, Lizi

Background : The LKB1 tumor suppressor gene is commonly inactivated in non-small cell lung carcinomas (NSCLC), a major form of lung cancer. Targeted therapies for LKB1-inactivated lung cancer are currently unavailable. Identification of critical signaling components downstream of LKB1 inactivation has the potential to uncover rational therapeutic targets. Here we investigated the role of INSL4, a member of the insulin/IGF/relaxin superfamily, in LKB1-inactivated NSCLCs. Methods : INSL4 [...]

Menée à l'aide de modèles murins de cancer du poumon présentant la mutation KrasG12D, cette étude met notamment en évidence des mécanismes par lesquels la surexpression du récepteur transmembranaire PCDH7 favorise la tumorigenèse

Modulation of mutant KrasG12D-driven lung tumorigenesis in vivo by gain or loss of PCDH7 function

Zhou, Xiaorong ; Padanad, Mahesh S. ; Evers, Bret M. ; Smith, Bethany ; Novaresi, Nicole ; Suresh, Shruthy ; Richardson, James A. ; Stein, Emily ; Zhu, JIngfei ; Hammer, Robert E. ; Donnell, Kathryn A.

PROTOCADHERIN 7 (PCDH7), a transmembrane receptor and member of the Cadherin superfamily, is frequently overexpressed in lung adenocarcinoma and is associated with poor clinical outcome. While PCDH7 was recently shown to promote transformation and facilitate brain metastasis in lung and breast cancers, decreased PCDH7 expression has also been documented in colorectal, gastric, and invasive bladder cancers. These data suggest context-dependent functions for PCDH7 in distinct tumor types. Given [...]

Cet article passe en revue les travaux récents sur les mécanismes par lesquels la famille de protéines SATB, impliquées dans l'organisation de la chromatine, régulent la progression tumorale

SATB family chromatin organizers as master regulators of tumor progression

Naik, Rutika ; Galande, Sanjeev

SATB (Special AT-rich binding protein) family proteins have emerged as key regulators that integrate higher-order chromatin organization with the regulation of gene expression. Studies over the past decade have elucidated the specific roles of SATB1 and SATB2, two closely related members of this family, in cancer progression. SATB family chromatin organizers play diverse and important roles in regulating the dynamic equilibrium of apoptosis, cell invasion, metastasis, proliferation, [...]

Menée sur des lignées cellulaires et à l'aide de modèles murins de cancer de la prostate, cette étude met en évidence le rôle joué par des anomalies du micro-environnement tumoral liées à l'âge dans la progression des tumeurs

The Aged Microenvironment Influences the Tumorigenic Potential of Malignant Prostate Epithelial Cells

Bianchi-Frias, Daniella ; Damodarasamy, Mamatha ; Hernandez, Susana A. ; Gil da Costa, Rui M. ; Vakar-Lopez, Funda ; Coleman, Ilsa M. ; Reed, May J. ; Nelson, Peter S.

The incidence of prostate cancer is directly linked to age, but age-associated changes that facilitate prostate cancer development and progression are poorly understood. This study investigated age-related changes in the prostate microenvironment for their influence on prostate cancer behavior. Prostate cancer cells implanted orthotopically into the prostate demonstrated accelerated tumor growth in aged compared with young mice. Metastatic lesions following intravenous injection were also more [...]

Cet article passe en revue les travaux récents sur les mécanismes par lesquels, de façon indépendante de la protéine p53 ou en coopération avec elle, les cellules tumorales s'adaptent à une instabilité chromosomique

Tolerance of Chromosomal Instability in Cancer: Mechanisms and Therapeutic Opportunities

Grönroos, Eva ; López-García, Carlos

Chromosomal instability (CIN) is the result of ongoing changes in the number (aneuploidy) and structure of chromosomes. CIN is induced by chromosome missegregation in mitosis and leads to karyotypic diversity within the cancer cell population, thereby adding to intratumor heterogeneity. Regardless of the overall pro-oncogenic function of CIN, its onset is typically detrimental for cell fitness and thus tumors must develop CIN-tolerance mechanisms in order to propagate. There is overwhelming [...]