A partir d'une analyse de 10 250 génomes issus d'échantillons tumoraux prélevés sur des patients atteints d'un cancer (36 types différents), cette étude identifie la présence, dans 7 à 12% des cancers gastriques, d'une signature mutationnelle suggérant l'intérêt d'un traitement à base de sels de platine ou d'inhibiteurs de PARP pour les patients dont les tumeurs présentent ces gènes mutés

A mutational signature in gastric cancer suggests therapeutic strategies

Alexandrov, Ludmil B. ; Nik-Zainal, Serena ; Siu, Hoi Cheong ; Leung, Suet Yi ; Stratton, Michael R.

Targeting defects in the DNA repair machinery of neoplastic cells, for example, those due to inactivating BRCA1 and/or BRCA2 mutations, has been used for developing new therapies in certain types of breast, ovarian and pancreatic cancers. Recently, a mutational signature was associated with failure of double-strand DNA break repair by homologous recombination based on its high mutational burden in samples harbouring BRCA1 or BRCA2 mutations. In pancreatic cancer, all responders to platinum [...]

Menée sur 10 patients atteints d'un cancer gastro-intestinal métastatique, cette étude analyse la capacité des lymphocytes infiltrant les tumeurs à reconnaître les néo-épitopes dérivés des mutations somatiques exprimées par les tumeurs

Immunogenicity of somatic mutations in human gastrointestinal cancers

Tran, Eric ; Ahmadzadeh, Mojgan ; Lu, Yong-Chen ; Gros, Alena ; Turcotte, Simon ; Robbins, Paul F. ; Gartner, Jared J. ; Zheng, Zhili ; Li, Yong F. ; Ray, Satyajit ; Wunderlich, John R. ; Somerville, Robert P. ; Rosenberg, Steven A.

It is unknown whether the human immune system frequently mounts a T-cell response against mutations expressed by common epithelial cancers. Using a next-generation sequencing approach combined with high-throughput immunologic screening, we demonstrated that tumor-infiltrating lymphocytes (TIL) from 9/10 patients with metastatic gastrointestinal cancers contained CD4+ and/or CD8+ T cells that recognized one to three neo-epitopes derived from somatic mutations expressed by the patient's own [...]

Menée sur 98 patients atteints d'une macroglobulinémie de Waldenstrom, cette étude française analyse le spectre des mutations du gène CXCR4 et met notamment en évidence une association entre ces mutations et un gain du chromosome 4, un gain de la région chromosomique Xq et une délétion de la région 6q

Genomic landscape of CXCR4 mutations in Waldenstrom's Macroglobulinemia

Poulain, Stephanie ; Roumier, Christophe ; Venet-Caillault, Aurelie ; Figeac, Martin ; HERBAUX, Charles ; Marot, Guillemette ; DOYE, Emmanuelle ; Bertrand, Elisabeth ; Geffroy, Sandrine ; LEPRETRE, Frederic ; Nibourel, Olivier ; DECAMBRON, Audrey ; Boyle, Eileen ; Renneville, Aline ; Tricot, Sabine ; Daudignon, Agnes ; Quesnel, Bruno ; Duthilleul, Patrick ; Preudhomme, Claude ; Leleu, Xavier

Purpose: Whole-genome sequencing has revealed MYD88 L265P and CXCR4 mutations (CXCR4mut) as the most prevalent somatic mutations in Waldenstrom's macroglobulinemia (WM). CXCR4 mutation has proved to be of critical importance in WM, in part due to its role as a mechanism of resistance to several agents. We have therefore sought to unravel the different aspects of CXCR4 mutations in WM. Experimental Design : We have scanned the 2 coding exons of CXCR4 in WM using deep next generation sequencing [...]

A partir d'une analyse de 501 exomes issus d'échantillons tumoraux prélevés sur des patients atteints d'un mélanome, cette étude identifie, dans 5% des cas, des mutations inactivant le gène suppresseur de tumeurs RASA2

Recurrent inactivating RASA2 mutations in melanoma

Arafeh, Rand ; Qutob, Nouar ; Emmanuel, Rafi ; Keren-Paz, Alona ; Madore, Jason ; Elkahloun, Abdel ; Wilmott, James S. ; Gartner, Jared J. ; Di Pizio, Antonella ; Winograd-Katz, Sabina ; Sindiri, Sivasish ; Rotkopf, Ron ; Dutton-Regester, Ken ; Johansson, Peter ; Pritchard, Antonia L. ; Waddell, Nicola ; Hill, Victoria K. ; Lin, Jimmy C. ; Hevroni, Yael ; Rosenberg, Steven A. ; Khan, Javed ; Ben-Dor, Shifra ; Niv, Masha Y. ; Ulitsky, Igor ; Mann, Graham J. ; Scolyer, Richard A. ; Hayward, Nicholas K. ; Samuels, Yardena

Analysis of 501 melanoma exomes identified RASA2, encoding a RasGAP, as a tumor-suppressor gene mutated in 5% of melanomas. Recurrent loss-of-function mutations in RASA2 were found to increase RAS activation, melanoma cell growth and migration. RASA2 expression was lost in ≥30% of human melanomas and was associated with reduced patient survival. These findings identify RASA2 inactivation as a melanoma driver and highlight the importance of RasGAPs in cancer.

Menée sur des lignées cellulaires, cette étude met en évidence des mécanismes par lesquels le facteur de transcription NRF2 régule le développement d’un cancer du poumon non à petites cellules

NRF2 regulates serine biosynthesis in non-small cell lung cancer

DeNicola, Gina M. ; Chen, Pei-Hsuan ; Mullarky, Edouard ; Sudderth, Jessica A. ; Hu, Zeping ; Wu, David ; Tang, Hao ; Xie, Yang ; Asara, John M. ; Huffman, Kenneth E. ; Wistuba, Ignacio I. ; Minna, John D. ; DeBerardinis, Ralph J. ; Cantley, Lewis C.

Tumors have high energetic and anabolic needs for rapid cell growth and proliferation, and the serine biosynthetic pathway was recently identified as an important source of metabolic intermediates for these processes. We integrated metabolic tracing and transcriptional profiling of a large panel of non–small cell lung cancer (NSCLC) cell lines to characterize the activity and regulation of the serine/glycine biosynthetic pathway in NSCLC. Here we show that the activity of this pathway is highly [...]

Menée à l'aide de modèles murins, cette étude met en évidence des mécanismes par lesquels, en reprogrammant des cellules initiatrices de tumeurs, la voie de signalisation Yap favorise le développement d'un cancer du côlon

Yap-dependent reprogramming of Lgr5+ stem cells drives intestinal regeneration and cancer

Gregorieff, Alex ; Liu, Yu ; Inanlou, Mohammad R. ; Khomchuk, Yuliya ; Wrana, Jeffrey L.

The gut epithelium has remarkable self-renewal capacity that under homeostatic conditions is driven by Wnt signalling in Lgr5+ intestinal stem cells (ISCs). However, the mechanisms underlying ISC regeneration after injury remain poorly understood. The Hippo signalling pathway mediates tissue growth and is important for regeneration. Here we demonstrate in mice that Yap, a downstream transcriptional effector of Hippo, is critical for recovery of intestinal epithelium after exposure to ionizing [...]

Cet article passe en revue les travaux récents sur le rôle des caractéristiques mécaniques du microenvironnement dans la progression tumorale et le processus métastatique

Forcing through Tumor Metastasis: The Interplay between Tissue Rigidity and Epithelial–Mesenchymal Transition

Wei, Spencer C. ; Yang, Jing

The mechanical properties of the tumor microenvironment have been increasingly recognized as potent modulators of cell behavior and function. In particular, tissue rigidity is functionally important during tumor progression. In this review, we survey recent advances in our understanding of the role of tissue rigidity in tumor progression and metastasis, the mechanisms by which mechanical cues integrate with biochemical signals from the microenvironment, and the underlying mechanotransduction [...]

Menée à l'aide de modèles murins, cette étude met en évidence le rôle joué par des « monocytes patrouillant » dans la régulation du processus de formation de métastases pulmonaires

Patrolling monocytes control tumor metastasis to the lung

Hanna, Richard N. ; Cekic, Caglar ; Sag, Duygu ; Tacke, Robert ; Thomas, Graham D. ; Nowyhed, Heba ; Herrley, Erica ; Rasquinha, Nicole ; McArdle, Sara ; Wu, Runpei ; Peluso, Esther ; Metzger, Daniel ; Ichinose, Hiroshi ; Shaked, Iftach ; Chodaczek, Grzegorz ; Biswas, Subhra K. ; Hedrick, Catherine C.

The immune system plays an important role in regulating tumor growth and metastasis. For example, classical monocytes promote tumorigenesis and cancer metastasis; however, how nonclassical “patrolling” monocytes interact with tumors is unknown. Here we show that patrolling monocytes are enriched in the microvasculature of the lung and reduce tumor metastasis to lung in multiple mouse metastatic tumor models. Nr4a1-deficient mice, which specifically lack patrolling monocytes, showed increased [...]