A partir d'échantillons tumoraux prélevés sur un total de 184 patients atteints d'un cancer colorectal sans mutation du gène KRAS, puis menée à l'aide de xénogreffes sur des modèles murins, cette étude identifie des mutations dans un ensemble de gènes en association avec la réponse à une thérapie ciblée anti EGFR

The genomic landscape of response to EGFR blockade in colorectal cancer

Bertotti, Andrea ; Papp, Eniko ; Jones, Sian ; Adleff, Vilmos ; Anagnostou, Valsamo ; Lupo, Barbara ; Sausen, Mark ; Phallen, Jillian ; Hruban, Carolyn A. ; Tokheim, Collin ; Niknafs, Noushin ; Nesselbush, Monica ; Lytle, Karli ; Sassi, Francesco ; Cottino, Francesca ; Migliardi, Giorgia ; Zanella, Eugenia R. ; Ribero, Dario ; Russolillo, Nadia ; Mellano, Alfredo ; Muratore, Andrea ; Paraluppi, Gianluca ; Salizzoni, Mauro ; Marsoni, Silvia ; Kragh, Michael ; Lantto, Johan ; Cassingena, Andrea ; Li, Qing Kay ; Karchin, Rachel ; Scharpf, Robert ; Sartore-Bianchi, Andrea ; Siena, Salvatore ; Diaz Jr, Luis A. ; Trusolino, Livio ; Velculescu, Victor E.

Colorectal cancer is the third most common cancer worldwide, with 1.2 million patients diagnosed annually. In late-stage colorectal cancer, the most commonly used targeted therapies are the monoclonal antibodies cetuximab and panitumumab, which prevent epidermal growth factor receptor (EGFR) activation. Recent studies have identified alterations in KRAS and other genes as likely mechanisms of primary and secondary resistance to anti-EGFR antibody therapy. Despite these efforts, additional [...]

A partir d'échantillons de la tumeur primitive, de métastases cérébrales et de tissu sain prélevés sur 86 patients, cette étude met en évidence, chez la moitié des patients, la présence -dans les métastases- d'anomalies cliniquement pertinentes alors que ces anomalies n'avaient pas été détectées dans la tumeur primitive

Genomic Characterization of Brain Metastases Reveals Branched Evolution and Potential Therapeutic Targets

Brastianos, Priscilla K. ; Carter, Scott L. ; Santagata, Sandro ; Cahill, Daniel P. ; Taylor-Weiner, Amaro ; Jones, Robert T. ; Van Allen, Eliezer M. ; Lawrence, Michael S. ; Horowitz, Peleg M. ; Cibulskis, Kristian ; Ligon, Keith L. ; Tabernero, Josep ; Seoane, Joan ; Martinez-Saez, Elena ; Curry, William T. ; Dunn, Ian F. ; Paek, Sun Ha ; Park, Sung-Hye ; McKenna, Aaron ; Chevalier, Aaron ; Rosenberg, Mara ; Barker, Frederick G. ; Gill, Corey M. ; Van Hummelen, Paul ; Thorner, Aaron R. ; Johnson, Bruce E. ; Hoang, Mai P. ; Choueiri, Toni K. ; Signoretti, Sabina ; Sougnez, Carrie ; Rabin, Michael S. ; Lin, Nancy U. ; Winer, Eric P. ; Stemmer-Rachamimov, Anat ; Meyerson, Matthew ; Garraway, Levi ; Gabriel, Stacey ; Lander, Eric S. ; Beroukhim, Rameen ; Batchelor, Tracy T. ; Baselga, Jose ; Louis, David N. ; Getz, Gad ; Hahn, William C.

Brain metastases are associated with a dismal prognosis. Whether brain metastases harbor distinct genetic alterations beyond those observed in primary tumors is unknown. We performed whole-exome sequencing of 86 matched brain metastases, primary tumors, and normal tissue. In all clonally related cancer samples, we observed branched evolution, where all metastatic and primary sites shared a common ancestor yet continued to evolve independently. In 53% of cases, we found potentially clinically [...]

Cet article passe en revue les travaux récents sur les caractéristiques des micro-environnements qui, dans un organe donné, permettent à des cellules cancéreuses de former une métastase

Surviving at a Distance: Organ-Specific Metastasis

Obenauf, Anna C. ; Massagué, Joan

The clinical manifestation of metastasis in a vital organ is the final stage of cancer progression and the main culprit of cancer-related mortality. Once established, metastasis is devastating, but only a small proportion of the cancer cells that leave a tumor succeed at infiltrating, surviving, and ultimately overtaking a distant organ. The bottlenecks that challenge cancer cells in newly invaded microenvironments are organ-specific and consequently demand distinct mechanisms for metastatic [...]

Cet article passe en revue les travaux récents sur les propriétés des cellules cancéreuses, seules ou en grappes, dans la circulation sanguine et dans le processus métastique

En Route to Metastasis: Circulating Tumor Cell Clusters and Epithelial-to-Mesenchymal Transition

Aceto, Nicola ; Toner, Mehmet ; Maheswaran, Shyamala ; Haber, Daniel A.

Blood-borne metastasis accounts for the vast majority of cancer-related deaths and it is fueled by the generation of circulating tumor cells (CTCs) from a primary tumor deposit. Recent technological advances have made it possible to characterize human CTCs as they travel within the bloodstream. CTCs are found both as single cells and as clusters of cells held together by intercellular junctions. Although less prevalent, CTC clusters appear to have greater metastatic potential than single CTCs [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels, en augmentant le recrutement de macrophages, la perte d'expression du gène LKB1 favorise la progression d'un cancer de l'endomètre

LKB1 loss promotes endometrial cancer progression via CCL2-dependent macrophage recruitment

Pena, Christopher G. ; Nakada, Yuji ; Saatcioglu, Hatice D. ; Aloisio, Gina M. ; Cuevas, Ileana ; Zhang, Song ; Miller, David S. ; Lea, Jayanthi S. ; Wong, Kwok-Kin ; DeBerardinis, Ralph J. ; Amelio, Antonio L. ; Brekken, Rolf A. ; Castrillon, Diego H.

Endometrial cancer is the most common gynecologic malignancy and the fourth most common malignancy in women. For most patients in whom the disease is confined to the uterus, treatment results in successful remission; however, there are no curative treatments for tumors that have progressed beyond the uterus. The serine/threonine kinase LKB1 has been identified as a potent suppressor of uterine cancer, but the biological modes of action of LKB1 in this context remain incompletely understood. [...]

Menée in vitro, in vivo et à l'aide de bases de données génomiques portant sur des patientes atteintes d'un cancer du col de l'utérus, cette étude met en évidence des mécanismes par lesquels, en interagissant avec la signalisation EGFR et l'oncoprotéine E6 du papillomavirus humain, la voie de signalisation Hippo/Yap régule la prolifération des cellules cancéreuses

The Hippo/YAP pathway interacts with EGFR signaling and HPV oncoproteins to regulate cervical cancer progression

He, Chunbo ; Mao, Dagan ; Hua, Guohua ; Lv, Xiangmin ; Chen, Xingcheng ; Angeletti, Peter C. ; Dong, Jixin ; Remmenga, Steven W. ; Rodabaugh, Kerry J. ; Zhou, Jin ; Lambert, Paul F. ; Yang, Peixin ; Davis, John S. ; Wang, Cheng

The Hippo signaling pathway controls organ size and tumorigenesis through a kinase cascade that inactivates Yes-associated protein (YAP). Here, we show that YAP plays a central role in controlling the progression of cervical cancer. Our results suggest that YAP expression is associated with a poor prognosis for cervical cancer. TGF-α and amphiregulin (AREG), via EGFR, inhibit the Hippo signaling pathway and activate YAP to induce cervical cancer cell proliferation and migration. Activated YAP [...]

Cet article passe en revue les travaux récents sur les origines cellulaires des tumeurs solides

Cellular Mechanisms Underlying Intertumoral Heterogeneity

Sutherland, Kate D. ; Visvader, Jane E.

Intertumoral heterogeneity is driven by a combination of intrinsic and extrinsic mechanisms. Intrinsic mechanisms include the genetic/epigenetic mutational profile of cells and the nature of the ‘cell of origin’. There is accumulating evidence that distinct ‘cells of origin’ within an organ can give rise to different subtypes of cancer. Tissue-specific stem and progenitor cells are the predominant targets exploited for tumor initiation. Extrinsic factors imposed by the microenvironment may also [...]