Menée à l'aide de cellules épithéliales sécrétoires de trompes de Fallope, cette étude met en évidence une association entre la réduction de l'expression des protéines SKP1 et CUL1 et une augmentation de l'expression de la cycline E1 et de l'instabilité chromosomique dans les cellules précurseurs des cancers séreux ovariens de haut grade

Reduced SKP1 and CUL1 expression underlies increases in Cyclin E1 and chromosome instability in cellular precursors of high-grade serous ovarian cancer

Lepage, Chloe Camille ; Palmer, Michaela Cora Lynn ; Farrell, Ally Catherina ; Neudorf, Nicole Marie ; Lichtensztejn, Zelda ; Nachtigal, Mark William ; McManus, Kirk James

Background : High-grade serous ovarian cancer (HGSOC) is the most common and lethal ovarian cancer histotype. Chromosome instability (CIN, an increased rate of chromosome gains and losses) is believed to play a fundamental role in the development and evolution of HGSOC. Importantly, overexpression of Cyclin E1 protein induces CIN, and genomic amplification of CCNE1 contributes to HGSOC pathogenesis in ~20% of patients. Cyclin E1 levels are normally regulated in a cell cycle-dependent manner by [...]

Cet article analyse le lien entre le mécanisme de cicatrisation et le processus métastatique

Cancer metastasis as a non-healing wound

Deyell, Matthew ; Garris, Christopher S. ; Laughney, Ashley M.

Most cancer deaths are caused by metastasis: recurrence of disease by disseminated tumour cells at sites distant from the primary tumour. Large numbers of disseminated tumour cells are released from the primary tumour, even during the early stages of tumour growth. However, only a minority survive as potential seeds for future metastatic outgrowths. These cells must adapt to a relatively inhospitable microenvironment, evade immune surveillance and progress from the micro- to macro-metastatic [...]

Menée in vitro et à l'aide de xénogreffes sur des modèles murins, cette étude met en évidence un mécanisme par lequel la protéine cytoplasmique DACT1 induite par le facteur TGFbêta, en réprimant la signalisation des glycoprotéines Wnt via la formation de condensats biomoléculaires, favorise le développement de métastases osseuses

TGF-β-induced DACT1 biomolecular condensates repress Wnt signalling to promote bone metastasis

Esposito, Mark ; Fang, Cao ; Cook, Katelyn C. ; Park, Nana ; Wei, Yong ; Spadazzi, Chiara ; Bracha, Dan ; Gunaratna, Ramesh T. ; Laevsky, Gary ; DeCoste, Christina J. ; Slabodkin, Hannah ; Brangwynne, Clifford P. ; Cristea, Ileana M. ; Kang, Yibin

The complexity of intracellular signalling requires both a diversity of molecular players and the sequestration of activity to unique compartments within the cell. Recent findings on the role of liquid–liquid phase separation provide a distinct mechanism for the spatial segregation of proteins to regulate signalling pathway crosstalk. Here, we discover that DACT1 is induced by TGFβ and forms protein condensates in the cytoplasm to repress Wnt signalling. These condensates do not localize to any [...]

Menée une vitro et à l'aide de modèles murins, cette étude met en évidence un mécanisme par lequel les cellules souches mésenchymateuses exprimant la nestine et le protéoglycane NG2 favorisent, via le facteur de croissance TGF-bêta2, la dormance des cellules cancéreuses mammaires disséminées dans la moelle osseuse

Bone marrow NG2+/Nestin+ mesenchymal stem cells drive DTC dormancy via TGF-β2

Nobre, Ana Rita ; Risson, Emma ; Singh, Deepak K. ; Di Martino, Julie S. ; Cheung, Julie F. ; Wang, Jiapeng ; Johnson, John ; Russnes, Hege G. ; Bravo-Cordero, Jose Javier ; Birbrair, Alexander ; Naume, Bjorn ; Azhar, Mohamad ; Frenette, Paul S. ; Aguirre-Ghiso, Julio A.

In the bone marrow (BM) microenvironment, where breast cancer (BC)-disseminated tumor cells (DTCs) can remain dormant for decades, NG2+/Nestin+ mesenchymal stem cells (MSCs) promote hematopoietic stem cell quiescence. Here we reveal that periarteriolar BM-resident NG2+/Nestin+ MSCs can also instruct BC DTCs to enter dormancy. NG2+/Nestin+ MSCs produce transforming growth factor (TGF)-β2 and bone morphogenetic protein (BMP)7 and activate a quiescence pathway dependent on TGFBRIII and BMPRII, [...]

Menée sur des cellules de gliome humain et à l'aide de données portant sur des patients atteints d'un gliome, cette étude met en évidence un mécanisme par lequel le catabolisme des lipides induit par l'autophagie favorise la progression tumorale pour surmonter le stress bioénergétique

Autophagy mediated lipid catabolism facilitates glioma progression to overcome bioenergetic crisis

Wang, Chenran ; Haas, Michael A. ; Yeo, Syn Kok ; Paul, Ritama ; Yang, Fuchun ; Vallabhapurapu, Subrahmanya ; Qi, Xiaoyang ; Plas, David R. ; Guan, Jun-Lin

Background : Activation of mTORC1 plays a significant role in cancer development and progression. However, the metabolic mechanisms to sustain mTORC1 activation of cancer cells within stressed environments are still under-appreciated. We recently revealed high autophagy activity in tumour cells with mTORC1 hyper-activation. Nevertheless, the functions and mechanisms of autophagy in regulating mTORC1 in glioma are not studied. Methods : Using glioma patient database and human glioma cells, we [...]

Cet article passe en revue les études concernant l'effet du microbiote humain sur le risque de cancer gastrointestinal, le pronostic et l'efficacité des traitements

The relationship between gastrointestinal cancers and the microbiota

LaCourse, Kaitlyn D. ; Johnston, Christopher D. ; Bullman, Susan

The contribution of the microbiota to disease progression and treatment efficacy is often neglected when determining who is at the highest risk of developing gastrointestinal cancers or designing treatment strategies for patients. We reviewed the current literature on the effect of the human microbiota on cancer risk, prognosis, and treatment efficacy. We highlight emerging research that seeks to identify microbial signatures as biomarkers for various gastrointestinal cancers, and discuss how [...]

Cet article analyse le rôle des protéines BET dans la carcinogenèse et passe en revue les progrès réalisés en matière d'inhibiteurs de BET et de biomarqueurs permettant de prédire l'activité de ces inhibiteurs

Achieving clinical success with BET inhibitors as anti-cancer agents

Shorstova, Tatiana ; Foulkes, William D. ; Witcher, Michael

The transcriptional upregulation of oncogenes is a driving force behind the progression of many tumours. However, until a decade ago, the concept of ‘switching off’ these oncogenic pathways represented a formidable challenge. Research has revealed that members of the bromo- and extra-terminal domain (BET) motif family are key activators of oncogenic networks in a spectrum of cancers; their function depends on their recruitment to chromatin through two bromodomains (BD1 and BD2). The advent of [...]

A partir de l'analyse de 17 métastases issues de 9 patients atteints d'un mélanome, cette étude identifie des peptides d'origine bactérienne associés aux antigènes HLA

Identification of bacteria-derived HLA-bound peptides in melanoma

Kalaora, Shelly ; Nagler, Adi ; Nejman, Deborah ; Alon, Michal ; Barbolin, Chaya ; Barnea, Eilon ; Ketelaars, Steven L. C. ; Cheng, Kuoyuan ; Vervier, Kevin ; Shental, Noam ; Bussi, Yuval ; Rotkopf, Ron ; Levy, Ronen ; Benedek, Gil ; Trabish, Sophie ; Dadosh, Tali ; Levin-Zaidman, Smadar ; Geller, Leore T. ; Wang, Kun ; Greenberg, Polina ; Yagel, Gal ; Peri, Aviyah ; Fuks, Garold ; Bhardwaj, Neerupma ; Reuben, Alexandre ; Hermida, Leandro ; Johnson, Sarah B. ; Galloway-Peña, Jessica R. ; Shropshire, William C. ; Bernatchez, Chantale ; Haymaker, Cara ; Arora, Reetakshi ; Roitman, Lior ; Eilam, Raya ; Weinberger, Adina ; Lotan-Pompan, Maya ; Lotem, Michal ; Admon, Arie ; Levin, Yishai ; Lawley, Trevor D. ; Adams, David J. ; Levesque, Mitchell P. ; Besser, Michal J. ; Schachter, Jacob ; Golani, Ofra ; Segal, Eran ; Geva-Zatorsky, Naama ; Ruppin, Eytan ; Kvistborg, Pia ; Peterson, Scott N. ; Wargo, Jennifer A. ; Straussman, Ravid ; Samuels, Yardena

A variety of species of bacteria are known to colonize human tumours1–11, proliferate within them and modulate immune function, which ultimately affects the survival of patients with cancer and their responses to treatment12–14. However, it is not known whether antigens derived from intracellular bacteria are presented by the human leukocyte antigen class I and II (HLA-I and HLA-II, respectively) molecules of tumour cells, or whether such antigens elicit a tumour-infiltrating T cell immune [...]