Cet article passe en revue les travaux récents sur les mécanismes par lesquels les micro-ARNs d'exosomes favorisent le développement d'une tumeur

Exosomal microRNAs (exomiRs): Small molecules with a big role in cancer

Bhome, Rahul ; Del Vecchio, Filippo ; Lee, Gui-Han ; Bullock, Marc D. ; Primrose, John N. ; Sayan, A. Emre ; Mirnezami, Alex H.

Exosomes are secreted vesicles which can transmit molecular cargo between cells. Exosomal microRNAs (exomiRs) have drawn much attention in recent years because there is increasing evidence to suggest that loading of microRNAs into exosomes is not a random process. Preclinical studies have identified functional roles for exomiRs in influencing many hallmarks of cancer. Mechanisms underpinning these actions, such as exomiR receptors (“miRceptors”), are now becoming apparent. Even more exciting is [...]

Menée in vitro et in vivo sur des modèles de lymphome T angio-immunoblastique, cette étude met en évidence des mécanismes par lesquels la petite GTPase RHOA, lorsque son gène présente la mutation G17V, favorise la prolifération des cellules cancéreuses

RHOA G17V Induces T Follicular Helper Cell Specification and Promotes Lymphomagenesis

Cortes, Jose R. ; Ambesi-Impiombato, Alberto ; Couronne, Lucile ; Quinn, S. Aidan ; Kim, Christine S. ; da Silva Almeida, Ana C. ; West, Zachary ; Belver, Laura ; Martin, Marta Sanchez ; Scourzic, Laurianne ; Bhagat, Govind ; Bernard, Olivier A. ; Ferrando, Adolfo A. ; Palomero, Teresa

Angioimmunoblastic T cell lymphoma (AITL) is an aggressive tumor derived from malignant transformation of T follicular helper (Tfh) cells. AITL is characterized by loss-of-function mutations in Ten-Eleven Translocation 2 (TET2) epigenetic tumor suppressor and a highly recurrent mutation (p.Gly17Val) in the RHOA small GTPase. Yet, the specific role of RHOA G17V in AITL remains unknown. Expression of Rhoa G17V in CD4+ T cells induces Tfh cell specification; increased proliferation associated with [...]

Menée sur des lignées cellulaires de glioblastome et à l'aide de xénogreffes, cette étude met en évidence des mécanismes par lesquels, en régulant la signalisation EGFR/STAT3, la protéine TRIM59 favorise la prolifération des cellules cancéreuses

TRIM59 promotes gliomagenesis by inhibiting TC45 dephosphorylation of STAT3

Sang, Youzhou ; Li, Yanxin ; Song, Lina ; Alvarez, Angel A. ; Zhang, Weiwei ; Lv, Deguan ; Tang, Jianming ; Liu, Feng ; Chang, Zhijie ; Hatakeyama, Shigetsugu ; Hu, Bo ; Cheng, Shi-Yuan ; Feng, Haizhong

Aberrant epidermal growth factor receptor (EGFR) signaling is a common driver of glioblastoma (GBM) pathogenesis, however, the downstream effectors that sustain this oncogenic pathway remain unclarified. Here we demonstrate that tripartite motif-containing protein 59 (TRIM59) acts as a new downstream effector of EGFR signaling by regulating STAT3 activation in GBM. EGFR signaling led to TRIM59 upregulation through SOX9 and enhanced the interaction between TRIM59 and nuclear STAT3, which [...]

Cet article passe en revue les travaux récents sur le rôle joué par des agrégats de cellules tumorales circulantes dans le processus métastatique

Perspective on Circulating Tumor Cell Clusters: Why It Takes a Village to Metastasize

Giuliano, Mario ; Shaikh, Anum ; Lo, Hin Ching ; Arpino, Grazia ; De Placido, Sabino ; Zhang, Xiang H. ; Cristofanilli, Massimo ; Schiff, Rachel ; Trivedi, Meghana V.

Circulating tumor cell (CTC) clusters may represent one of the key mechanisms initiating the metastasis process. However, the series of pathophysiologic events by which CTC clusters originate, enter the circulation, and reach the distant sites remain to be identified. The cellular and molecular mechanisms that provide survival advantage for CTC clusters during the transit in the blood stream are also still largely unknown. Understanding the biology of CTC clusters is critical to assess this [...]

Menée in vitro et in vivo sur des modèles de mélanome, cette étude met en évidence des mécanismes par lesquels, en régulant la signalisation AKT, l'enzyme PHLPP1 exerce une fonction de suppresseur du processus métastatique

PHLPP1 mediates melanoma metastasis suppression through repressing AKT2 activation

Yu, Yanlin ; Dai, Meng ; Lu, Andrew ; Yu, Ellen ; Merlino, Glenn

PI3K/AKT pathway activation is thought to be a driving force in metastatic melanomas. Members of the pleckstrin homology (PH) domain leucine-rich repeat protein Ser/Thr specific phosphatase family (PHLPP1 and PHLPP2) can regulate AKT activation. By dephosphorylating specific serine residues in the hydrophobic motif, PHLPP1 and PHLPP2 restrain AKT signalings, thereby regulating cell proliferation and survival. We here show that PHLPP1 expression was significantly downregulated or lost and [...]

A l'aide de lignées cellulaires de myélome multiple et à l'aide de xénogreffes sur des modèles murins, cette étude met en évidence des mécanismes par lesquels la protéine HSF1 favorise la croissance tumorale

HSF1 Is Essential for Myeloma Cell Survival and A Promising Therapeutic Target

Fok, Jacqueline H. L. ; Hedayat, Somaieh ; Zhang, Lei ; Aronson, Lauren I. ; Mirabella, Fabio ; Pawlyn, Charlotte ; Bright, Michael D. ; Wardell, Christopher P. ; Keats, Jonathan J. ; De Billy, Emmanuel ; Rye, Carl S. ; Chessum, Nicola E. A. ; Jones, Keith ; Morgan, Gareth J. ; Eccles, Suzanne A. ; Workman, Paul ; Davies, Faith E.

Purpose: Myeloma is a plasma cell malignancy characterized by the overproduction of immunoglobulin, and is therefore susceptible to therapies targeting protein homeostasis. We hypothesized that heat shock factor 1 (HSF1) was an attractive therapeutic target for myeloma due to its direct regulation of transcriptional programs implicated in both protein homeostasis and the oncogenic phenotype. Here, we interrogate HSF1 as a therapeutic target in myeloma using bioinformatic, genetic, and [...]

Menée sur des lignées cellulaires de cancer de l'ovaire et à l'aide de xénogreffes, cette étude met en évidence des mécanismes par lesquels, en augmentant l'expression du récepteur des acides gras CD36 dans les cellules cancéreuses, les adipocytes de l'épiploon favorisent la progression tumorale et le processus métastatique

Adipocyte-induced CD36 expression drives ovarian cancer progression and metastasis

Ladanyi, Andras ; Mukherjee, Abir ; Kenny, Hilary A. ; Johnson, Alyssa ; Mitra, Anirban K. ; Sundaresan, Sinju ; Nieman, Kristin M. ; Pascual, Gloria ; Benitah, Salvador Aznar ; Montag, Anthony ; Yamada, S. Diane ; Abumrad, Nada A. ; Lengyel, Ernst

Ovarian cancer (OvCa) is characterized by widespread and rapid metastasis in the peritoneal cavity. Visceral adipocytes promote this process by providing fatty acids (FAs) for tumour growth. However, the exact mechanism of FA transfer from adipocytes to cancer cells remains unknown. This study shows that OvCa cells co-cultured with primary human omental adipocytes express high levels of the FA receptor, CD36, in the plasma membrane, thereby facilitating exogenous FA uptake. Depriving OvCa cells [...]

A l'aide d'échantillons tumoraux prélevés sur des patients atteints d'un cancer colorectal, puis à l'aide de xénogreffes, cette étude met en évidence des mécanismes par lesquels des agrégats de cellules cancéreuses épithéliales favorisent le processus métastatique de tumeurs présentant une hyperméthylation

Tumour spheres with inverted polarity drive the formation of peritoneal metastases in patients with hypermethylated colorectal carcinomas

Zajac, Olivier ; Raingeaud, Joel ; Libanje, Fotine ; Lefebvre, Celine ; Sabino, Dora ; Martins, Isabelle ; Roy, Pétronille ; Benatar, Clara ; Canet-Jourdan, Charlotte ; Azorin, Paula ; Polrot, Mélanie ; Gonin, Patrick ; Benbarche, Salima ; Souquere, Sylvie ; Pierron, Gerard ; Nowak, Damien ; Bigot, Ludovic ; Ducreux, Michel ; Malka, David ; Lobry, Camille ; Scoazec, Jean-Yves ; Eveno, Clarisse ; Pocard, Marc ; Perfettini, Jean-Luc ; Elias, Dominique ; Dartigues, Peggy ; Goere, Diane ; Jaulin, Fanny

Metastases account for 90% of cancer-related deaths; thus, it is vital to understand the biology of tumour dissemination. Here, we collected and monitored >50 patient specimens ex vivo to investigate the cell biology of colorectal cancer (CRC) metastatic spread to the peritoneum. This reveals an unpredicted mode of dissemination. Large clusters of cancer epithelial cells displaying a robust outward apical pole, which we termed tumour spheres with inverted polarity (TSIPs), were observed [...]

A partir de travaux récents sur le rôle joué par la protéine kinase MELK dans les cancers chez l'humain, cette étude passe en revue les limites des outils utilisés en recherche, notamment les lignées cellulaires et les ARNs interférents, pour valider une cible thérapeutique

Challenges in validating candidate therapeutic targets in cancer

Settleman, Jeffrey ; Sawyers, Charles L. ; Hunter, Tony

More than 30 published articles have suggested that a protein kinase called MELK is an attractive therapeutic target in human cancer, but three recent reports describe compelling evidence that it is not. These reports highlight the caveats associated with some of the research tools that are commonly used to validate candidate therapeutic targets in cancer research.

Menée à l'aide de lignées cellulaires et de modèles murins, cette étude met en évidence des mécanismes par lesquels, en produisant les chimiokines CCL5 et XCL1, des cellules NK stimulent le recrutement de cellules dendritiques conventionnelles de type 1 dans le micro-environnement tumoral et, ainsi, favorisent le contrôle de la tumeur par le système immunitaire

NK Cells Stimulate Recruitment of cDC1 into the Tumor Microenvironment Promoting Cancer Immune Control

Böttcher, Jan P. ; Bonavita, Eduardo ; Chakravarty, Probir ; Blees, Hanna ; Cabeza-Cabrerizo, Mar ; Sammicheli, Stefano ; Rogers, Neil C. ; Sahai, Erik ; Zelenay, Santiago ; Reis e Sousa, Caetano

Conventional type 1 dendritic cells (cDC1) are critical for antitumor immunity, and their abundance within tumors is associated with immune-mediated rejection and the success of immunotherapy. Here, we show that cDC1 accumulation in mouse tumors often depends on natural killer (NK) cells that produce the cDC1 chemoattractants CCL5 and XCL1. Similarly, in human cancers, intratumoral CCL5, XCL1, and XCL2 transcripts closely correlate with gene signatures of both NK cells and cDC1 and are [...]

A partir de données immunologiques et épidémiologiques, cette étude présente un modèle suggérant que la principale raison pour laquelle le cancer est une maladie liée à l'âge n'est pas l'accumulation de mutations mais le déclin du système immunitaire

Thymic involution and rising disease incidence with age

Palmer, Sam ; Albergante, Luca ; Blackburn, Clare C. ; Newman, T. J.

Understanding the risk factors of carcinogenesis is a major goal of biomedical research. Historically, the focus has been on the role of somatic mutations, and the reason for cancer typically occurring late in life is predominantly attributed to a gradual accumulation of such mutations. We challenge that view and propose that the decline of the immune system is the primary reason why cancer is an age-related disease. The immunological model featured here captures risk profiles for many cancer [...]