Menée in vitro et à l'aide d'un modèle murin transgénique, cette étude met en évidence un mécanisme par lequel la modification du transcriptome induite par la mutation K27M de l'histone H3 favorise la tumorigenèse en activant de façon épigénétique l'axe RAS/MYC

Epigenetic activation of a RAS/MYC axis in H3.3K27M-driven cancer

Pajovic, Sanja ; Siddaway, Robert ; Bridge, Taylor ; Sheth, Javal ; Rakopoulos, Patricia ; Kim, Byungjin ; Ryall, Scott ; Agnihotri, Sameer ; Phillips, Lauren ; Yu, Man ; Li, Christopher ; Milos, Scott ; Patel, Palak ; Srikanthan, Dilakshan ; Huang, Annie ; Hawkins, Cynthia

Histone H3 lysine 27 (H3K27M) mutations represent the canonical oncohistone, occurring frequently in midline gliomas but also identified in haematopoietic malignancies and carcinomas. H3K27M functions, at least in part, through widespread changes in H3K27 trimethylation but its role in tumour initiation remains obscure. To address this, we created a transgenic mouse expressing H3.3K27M in diverse progenitor cell populations. H3.3K27M expression drives tumorigenesis in multiple tissues, which is [...]

Menée à l'aide de lignées de cellules cancéreuses, cette étude met en évidence un mécanisme par lequel le suppresseur de tumeur ARF, en ciblant les phosphatases PPM1G/PP2Cgamma, inhibe la fonction transcriptionnelle du facteur NF-kappa

The ARF tumor suppressor targets PPM1G/PP2Cgamma to counteract NF-kappaB transcription tuning cell survival and the inflammatory response

Hyder, Usman ; McCann, Jennifer L. ; Wang, Jinli ; Fung, Victor ; Bayo, Juan ; D’Orso, Iván

The NF-κB signaling pathway is critical for cellular responses to cell-extrinsic insults. Its dysregulation impacts cancer patients’ survival and response to available therapeutics. NF-κB utilizes the PPM1G phosphatase as a coactivator to induce inflammatory and cell survival programs in response to proinflammatory cytokines. However, how PPM1G activity is regulated to facilitate tunable control and insult resolution remains enigmatic. We take advantage of biochemical and genetic approaches and [...]

Cet article passe en revue les mécanismes par lesquels les voies de régulation de l'endocytose affectent les différentes phases du processus métastatique

Endocytosis: a pivotal pathway for regulating metastasis

Khan, Imran ; Steeg, Patricia S.

A potentially important aspect in the regulation of tumour metastasis is endocytosis. This process consists of internalisation of cell-surface receptors via pinocytosis, phagocytosis or receptor-mediated endocytosis, the latter of which includes clathrin-, caveolae- and non-clathrin or caveolae-mediated mechanisms. Endocytosis then progresses through several intracellular compartments for sorting and routing of cargo, ending in lysosomal degradation, recycling back to the cell surface or [...]

Cet article présente les mécanismes d'adaptation développés par les cellules tumorales circulantes pour résister aux contraintes mécaniques de la microcirculation et explique la façon dont ces forces mécaniques peuvent modifier les cellules cancéreuses et les rendre plus agressives

Squeezing through the microcirculation: survival adaptations of circulating tumour cells to seed metastasis

Perea Paizal, Julia ; Au, Sam H. ; Bakal, Chris

During metastasis, tumour cells navigating the vascular circulatory system—circulating tumour cells (CTCs)—encounter capillary beds, where they start the process of extravasation. Biomechanical constriction forces exerted by the microcirculation compromise the survival of tumour cells within capillaries, but a proportion of CTCs manage to successfully extravasate and colonise distant sites. Despite the profound importance of this step in the progression of metastatic cancers, the factors about [...]

Cet article analyse la relation entre les caractéristiques de la transition épithélio-mésenchymateuse induite par les récepteurs du ligand TRAIL, le phénotype des cellules cancéreuses et la réponse de ces dernières aux traitements

TRAIL receptor-induced features of epithelial-to-mesenchymal transition increase tumour phenotypic heterogeneity: potential cell survival mechanisms

Peyre, Ludovic ; Meyer, Mickael ; Hofman, Paul ; Roux, Jérémie

The continuing efforts to exploit the death receptor agonists, such as the tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), for cancer therapy, have largely been impaired by the anti-apoptotic and pro-survival signalling pathways leading to drug resistance. Cell migration, invasion, differentiation, immune evasion and anoikis resistance are plastic processes sharing features of the epithelial-to-mesenchymal transition (EMT) that have been shown to give cancer cells the [...]

Menée in vitro et à l'aide d'un modèle murin d'adénocarcinome canalaire du pancréas, cette étude met en évidence un mécanisme par lequel les axones périphériques, en sécrétant la sérine (un acide aminé), favorise la traduction des ARNs messagers et la croissance des cellules tumorales privées de sérine et de glycine

Neurons Release Serine to Support mRNA Translation in Pancreatic Cancer

Banh, Robert S. ; Biancur, Douglas E. ; Yamamoto, Keisuke ; Sohn, Albert S. W. ; Walters, Beth ; Kuljanin, Miljan ; Gikandi, Ajami ; Wang, Huamin ; Mancias, Joseph D. ; Schneider, Robert J. ; Pacold, Michael E. ; Kimmelman, Alec C.

Pancreatic ductal adenocarcinoma (PDAC) tumors have a nutrient-poor, desmoplastic, and highly innervated tumor microenvironment. Although neurons can release stimulatory factors to accelerate PDAC tumorigenesis, the metabolic contribution of peripheral axons has not been explored. We found that peripheral axons release serine (Ser) to support the growth of exogenous Ser (exSer)-dependent PDAC cells during Ser/Gly (glycine) deprivation. Ser deprivation resulted in ribosomal stalling on two of [...]

Menée à partir d'une analyse protéomique et du séquençage de microARNs d'exosomes issus de cellules colorectales cancéreuses infectées ou non par la bactérie Fusobacterium nucleatum, cette étude met en évidence un mécanisme par lequel les exosomes issus de cette bactérie favorisent le processus métastatique en transportant de manière sélective les microARNs miR-1246/92b-3p/27a-3 et la chimiokine CXCL16

Exosomes derived from Fusobacterium nucleatum-infected colorectal cancer cells facilitate tumour metastasis by selectively carrying miR-1246/92b-3p/27a-3p and CXCL16

Guo, Songhe ; Chen, Jun ; Chen, Fangfang ; Zeng, Qiuyao ; Liu, Wan-Li ; Zhang, Ge

Objective : Exosomes released from tumour cells are packed with unique RNA and protein cargo, and they are emerging as an important mediator in the communication network that promotes tumour progression. The facultative intracellular bacterium Fusobacterium nucleatum (Fn) is an important colorectal cancer (CRC)-associated bacterium. To date, the function of exosomes from Fn-infected CRC cells has not been explored. Design : Exosomes were isolated by sequential differential centrifugation and [...]

Menée in vitro et in vivo, cette étude met en évidence un mécanisme par lequel les cellules myéloïdes du système nerveux central, via la chimiokine CXCL10, favorise l'immunosuppression dans les régions cérébrales où résident des métastases

CNS-Native Myeloid Cells Drive Immune Suppression in the Brain Metastatic Niche through Cxcl10

Guldner, Ian H. ; Wang, Qingfei ; Yang, Lin ; Golomb, Samantha M. ; Zhao, Zhuo ; Lopez, Jacqueline A. ; Brunory, Abigail ; Howe, Erin N. ; Zhang, Yizhe ; Palakurthi, Bhavana ; Barron, Martin ; Gao, Hongyu ; Xuei, Xiaoling ; Liu, Yunlong ; Li, Jun ; Chen, Danny Z. ; Landreth, Gary E. ; Zhang, Siyuan

Brain metastasis (br-met) develops in an immunologically unique br-met niche. Central nervous system-native myeloid cells (CNS-myeloids) and bone-marrow-derived myeloid cells (BMDMs) cooperatively regulate brain immunity. The phenotypic heterogeneity and specific roles of these myeloid subsets in shaping the br-met niche to regulate br-met outgrowth have not been fully revealed. Applying multimodal single-cell analyses, we elucidated a heterogeneous but spatially defined CNS-myeloid response [...]

Cette étude analyse les caractéristiques génétiques et moléculaires de 25 lignées d'organoïdes de tumeurs gastro-entéro-pancréatiques neuro-endocrines

An Organoid Biobank of Neuroendocrine Neoplasms Enables Genotype-Phenotype Mapping

Kawasaki, Kenta ; Toshimitsu, Kohta ; Matano, Mami ; Fujita, Masashi ; Fujii, Masayuki ; Togasaki, Kazuhiro ; Ebisudani, Toshiki ; Shimokawa, Mariko ; Takano, Ai ; Takahashi, Sirirat ; Ohta, Yuki ; Nanki, Kosaku ; Igarashi, Ryo ; Ishimaru, Kazuhiro ; Ishida, Hiroki ; Sukawa, Yasutaka ; Sugimoto, Shinya ; Saito, Yoshimasa ; Maejima, Kazuhiro ; Sasagawa, Shota ; Lee, Hwajin ; Kim, Hong-Gee ; Ha, Kyungsik ; Hamamoto, Junko ; Fukunaga, Koichi ; Maekawa, Aya ; Tanabe, Minoru ; Ishihara, Soichiro ; Hamamoto, Yasuo ; Yasuda, Hiroyuki ; Sekine, Shigeki ; Kudo, Atsushi ; Kitagawa, Yuko ; Kanai, Takanori ; Nakagawa, Hidewaki ; Sato, Toshiro

Gastroenteropancreatic (GEP) neuroendocrine neoplasm (NEN) that consists of neuroendocrine tumor and neuroendocrine carcinoma (NEC) is a lethal but under-investigated disease owing to its rarity. To fill the scarcity of clinically relevant models of GEP-NEN, we here established 25 lines of NEN organoids and performed their comprehensive molecular characterization. GEP-NEN organoids recapitulated pathohistological and functional phenotypes of the original tumors. Whole-genome sequencing revealed [...]

Menée sur des cellules de cancer gastrique, cette étude met en évidence le rôle de la voie de la biosynthèse des acides gras poly-insaturés dans la sensibilité des cellules cancéreuses à la ferroptose

Polyunsaturated fatty acid biosynthesis pathway determines ferroptosis sensitivity in gastric cancer

Lee, Ji-Yoon ; Nam, Miso ; Son, Hye Young ; Hyun, Kwangbeom ; Jang, Seo Young ; Kim, Jong Woo ; Kim, Min Wook ; Jung, Youngae ; Jang, Eunji ; Yoon, Seon-Jin ; Kim, Jungeun ; Kim, Jihye ; Seo, Jinho ; Min, Jeong-Ki ; Oh, Kyoung-Jin ; Han, Baek-Soo ; Kim, Won Kon ; Bae, Kwang-Hee ; Song, Jaewhan ; Kim, Jaehoon ; Huh, Yong-Min ; Hwang, Geum-Sook ; Lee, Eun-Woo ; Lee, Sang Chul

Phosphatidylethanolamine (PE)-linked arachidonic acid (AA) and adrenic acid (AdA) are well-known substrates for lipid peroxidation, which are indispensable for ferroptosis, an iron-dependent regulated necrosis. However, how cells differentially regulate the intracellular pools of AA and AdA is not fully understood. Here, elongation of very long-chain fatty acid protein 5 (ELOVL5) and fatty acid desaturase 1 (FADS1) are differentially expressed in gastric cancer cells, discriminating the [...]

Menée notamment à l'aide de cellules mononucléées extraites d'échantillons sanguins issus de donneurs sains et de patients atteints d'un cancer avec haute instabilité des microsatellites, cette étude identifie des néo-antigènes comportant des épitopes hautement immunogènes résultant de mutations avec décalage du cadre de lecture communes à plusieurs types tumoraux (endomètre, côlon-rectum et estomac)

Shared Immunogenic Poly-Epitope Frameshift Mutations in Microsatellite Unstable Tumors

Roudko, Vladimir ; Bozkus, Cansu Cimen ; Orfanelli, Theofano ; McClain, Christopher B. ; Carr, Caitlin ; O’Donnell, Timothy ; Chakraborty, Lauren ; Samstein, Robert ; Huang, Kuan-lin ; Blank, Stephanie V. ; Greenbaum, Benjamin ; Bhardwaj, Nina

Microsatellite instability-high (MSI-H) tumors are characterized by high tumor mutation burden and responsiveness to checkpoint blockade. We identified tumor-specific frameshifts encoding multiple epitopes that originated from indel mutations shared among patients with MSI-H endometrial, colorectal, and stomach cancers. Epitopes derived from these shared frameshifts have high population occurrence rates, wide presence in many tumor subclones, and are predicted to bind to the most frequent MHC [...]