Menée in vitro, à l'aide d'un modèle murin et de 90 échantillons tumoraux fixés au formaldéhyde et inclus en paraffine après prélèvement sur des patients atteints d'un carcinome hépatocellulaire, cette étude met en évidence un mécanisme par lequel la protéine kinase de la fructokinase A, en phosphorylant la protéine p62, favorise la carcinogenèse et la réponse des cellules cancéreuses au stress oxydant

The protein kinase activity of fructokinase A specifies the antioxidant responses of tumor cells by phosphorylating p62

Xu, Daqian ; Li, Xinjian ; Shao, Fei ; Lv, Guishuai ; Lv, Hongwei ; Lee, Jong-Ho ; Qian, Xu ; Wang, Zheng ; Xia, Yan ; Du, Linyong ; Zheng, Yanhua ; Wang, Hongyang ; Lyu, Jianxin ; Lu, Zhimin

Cancer cells often encounter oxidative stress. However, it is unclear whether normal and cancer cells differentially respond to oxidative stress. Here, we demonstrated that under oxidative stress, hepatocellular carcinoma (HCC) cells exhibit increased antioxidative response and survival rates compared to normal hepatocytes. Oxidative stimulation induces HCC-specifically expressed fructokinase A (KHK-A) phosphorylation at S80 by 5′-adenosine monophosphate-activated protein kinase. KHK-A in turn [...]

Cet article présente des mécanismes de reprogrammation métabolique et épigénétique de cellules souches lors de la cancérogenèse induite par l'arsenic

Metabolic and epigenetic reprogramming in the arsenic-induced cancer stem cells

Li, Lingzhi ; Bi, Zhuoyu ; Wadgaonkar, Priya ; Lu, Yongju ; Zhang, Qian ; Fu, Yao ; Thakur, Chitra ; Wang, Li ; Chen, Fei

At present, the belief that genetic mutations control every aspect of tumorigenesis is still very popular. Even for the highly debated “bad luck” theory of cancers, it ascertained that random mutation of genes during the self-renewal of somatic stem cells is responsible for cancer initiation. Logically, most of the new therapeutic strategies so far, from molecular targeting to precision medicine or personalized medicine, are genome-obsessed and focused on identifying and targeting these mutated [...]

Menée in vitro et in silico, cette étude met en évidence un mécanisme par lequel les protéines CHERP / SR140, via la régulation de l'épissage alternatif, favorisent la tumorigenèse des cellules du côlon

U2-related proteins CHERP and SR140 contribute to colorectal tumorigenesis via alternative splicing regulation

Wang, Qianqian ; Wang, Yue ; Liu, Yuguo ; Zhang, Chang ; Luo, Yangjun ; Guo, Ruochen ; Zhan, Zheng ; Wei, Ning ; Xie, Zhiqin ; Shen, Lei ; Wu, Guohao ; Wu, Wenwu ; Feng, Ying

Dysregulation of calcium homeostasis endoplasmic reticulum protein (CHERP) has been implicated in several cancers, but it remains elusive how CHERP contributes to cancer cell proliferation and cancer development. Here, we observed that CHERP and its binding partner SR140 are significantly upregulated in human clinical colorectal cancer tissues (CRC). CHERP and SR140 could form a protein complex to stabilize each other. Knockdown of CHERP or SR140 triggers double-stranded DNA breaks and cell [...]

Menée sur des cellules souches embryonnaires humaines, cette étude met en évidence le rôle du suppresseur de tumeur SMARCB1 dans la régulation des régions amplificatrices de l'ADN et la différenciation neurale des cellules souches

Tumor suppressor SMARCB1 suppresses super-enhancers to govern hESC lineage determination

Langer, Lee F. ; Ward, James M. ; Archer, Trevor K.

The SWI/SNF complex is a critical regulator of pluripotency in human embryonic stem cells (hESCs), and individual subunits have varied and specific roles during development and in diseases. The core subunit SMARCB1 is required for early embryonic survival, and mutations can give rise to atypical teratoid/rhabdoid tumors (AT/RTs) in the pediatric central nervous system. We report that in contrast to other studied systems, SMARCB1 represses bivalent genes in hESCs and antagonizes chromatin [...]

Menée à partir des données du projet "The Cancer Genome Atlas", cette étude identifie, à l'aide de l'intelligence artificielle basée sur la technologie des réseaux de neurones récurrents à mémoire court-terme et long terme, une série de mutations "passagères" impliquées dans la progression des cancers du côlon ou du poumon

In silico learning of tumor evolution through mutational time series

Auslander, Noam ; Wolf, Yuri I. ; Koonin, Eugene V.

Cancer is caused by the effects of somatic mutations known as drivers. Although a number of major cancer drivers have been identified, it is suspected that many more comparatively rare and conditional drivers exist, and the interactions between different cancer-associated mutations that might be relevant for tumor progression are not well understood. We applied an advanced neural network approach to learn the sequence of mutations and the mutational burden in colon and lung cancers and to [...]

Menée in vitro et à l'aide d'un modèle murin de cancer colorectal, cette étude met en évidence un mécanisme par lequel l'enzyme KRAS, en réprimant l'expression du facteur de régulation IRF2, favorise l'immunosuppression et la résistance des cellules cancéreuses aux inhibiteurs de points de contrôle immunitaires

KRAS-IRF2 Axis Drives Immune Suppression and Immune Therapy Resistance in Colorectal Cancer

Liao, Wenting ; Overman, Michael J. ; Boutin, Adam T. ; Shang, Xiaoying ; Zhao, Di ; Dey, Prasenjit ; Li, Jiexi ; Wang, Guocan ; Lan, Zhengdao ; Li, Jun ; Tang, Ming ; Jiang, Shan ; Ma, Xingdi ; Chen, Peiwen ; Katkhuda, Riham ; Korphaisarn, Krittiya ; Chakravarti, Deepavali ; Chang, Andrew ; Spring, Denise J. ; Chang, Qing ; Zhang, Jianhua ; Maru, Dipen M. ; Maeda, Dean Y. ; Zebala, John A. ; Kopetz, Scott ; Wang, Y. Alan ; DePinho, Ronald A.

The biological functions and mechanisms of oncogenic KRAS G12D (KRAS ∗) in resistance to immune checkpoint blockade (ICB) therapy are not fully understood. We demonstrate that KRAS ∗ represses the expression of interferon regulatory factor 2 (IRF2), which in turn directly represses CXCL3 expression. KRAS ∗-mediated repression of IRF2 results in high expression of CXCL3, which binds to CXCR2 on myeloid-derived suppressor cells and promotes their migration to the tumor microenvironment. Anti-PD-1 [...]

Menée sur des lignées cellulaires de cancer du sein, cette étude met en évidence le rôle de l'hélicase DDX5 dans l'activation de Fra-1, un facteur de transcription impliqué dans la croissance des cancers du sein triplement négatifs

Endogenous interaction profiling identifies DDX5 as an oncogenic coactivator of transcription factor Fra-1

He, Huan ; Song, Dandan ; Sinha, Indranil ; Hessling, Bernd ; Li, Xidan ; Haldosen, Lars-Arne ; Zhao, Chunyan

Fra-1, a member of the activator protein 1 (AP-1) family, is overexpressed in triple-negative breast cancer (TNBC) and plays crucial roles in tumor growth. Here we report the identification of 118 proteins interacting with endogenous chromatin-bound Fra-1 in TNBC cells, highlighting DDX5 as the most enriched Fra-1-interacting protein. DDX5, a previously unrecognized protein in the Fra-1 transcriptional network, shows extensive overlap with Fra-1 cistrome and transcriptome that are highly [...]

Menée à l'aide d'explants de glioblastomes humains et de modèles murins de gliomes, cette étude met en évidence un mécanisme par lequel l'interleukine 6 sécrétée par les cellules cancéreuses induit l'expression de PD-L1 à la surface des cellules myéloïdes périphériques immunosuppressives et favorise la croissance tumorale

Glioblastoma-Derived IL6 Induces Immunosuppressive Peripheral Myeloid Cell PD-L1 and Promotes Tumor Growth

Lamano, Jonathan B. ; Lamano, Jason Balquidera ; Li, Yuping D. ; DiDomenico, Joseph D. ; Choy, Winward ; Veliceasa, Dorina ; Oyon, Daniel E. ; Fakurnejad, Shayan ; Ampie, Leonel ; Kesavabhotla, Kartik ; Kaur, Rajwant ; Kaur, Gurvinder ; Biyashev, Dauren ; Unruh, Dusten J. ; Horbinski, Craig M. ; James, C. David ; Parsa, Andrew T. ; Bloch, Orin

Purpose : Upregulation of programmed death-ligand 1 (PD-L1) on circulating and tumor-infiltrating myeloid cells is a critical component of GBM-mediated immunosuppression that has been associated with diminished response to vaccine immunotherapy and poor survival. Although GBM-derived soluble factors have been implicated in myeloid PD-L1 expression, the identity of such factors has remained unknown. This study aimed to identify factors responsible for myeloid PD-L1 upregulation as potential [...]