La nostra ricerca sulla rigenerazione cardiaca è stata pubblicata su Nature Cell Biology!

The murine neonatal heart can regenerate after injury through cardiomyocyte (CM) proliferation, although this capacity markedly diminishes after the first week of life. Neuregulin-1 ( NRG1) administration has been proposed as a strategy to promote cardiac regeneration. Here, using loss- and gain-of-function genetic tools, we explore the role of the NRG1 co-receptor ERBB2 in cardiac regeneration. NRG1-induced CM proliferation diminished one week after birth owing to a reduction in ERBB2 expression. CM-specific Erbb2 knockout revealed that ERBB2 is required for CM proliferation at embryonic/neonatal stages. Induction of a constitutively active ERBB2 (ca ERBB2) in neonatal, juvenile and adult CMs resulted in cardiomegaly, characterized by extensive CM hypertrophy, dedifferentiation and proliferation, differentially mediated by ERK, AKT and GSK3β/ β-catenin signalling pathways. Transient induction of ca ERBB2 following myocardial infarction triggered CM dedifferentiation and proliferation followed by redifferentiation and regeneration. Thus, ERBB2 is both necessary for CM proliferation and sufficient to reactivate postnatal CM proliferative and regenerative potentials.

Vai all’articolo originale (in inglese): Gabriele D’Uva, Alla Aharonov, Mattia Lauriola, David Kain, Yfat Yahalom-Ronen, Silvia Carvalho, Karen Weisinger, Elad Bassat, Dana Rajchman, Oren Yifa, Marina Lysenko, Tal Konfino, Julius Hegesh, Ori Brenner, Michal Neeman, Yosef Yarden, Jonathan Leor, Rachel Sarig, Richard P Harvey and Eldad Tzahor. ERBB2 triggers mammalian heart regeneration by promoting cardiomyocyte dedifferentiation and proliferation. Nature Cell Biology, 2015

Scientific recognitions

MEDIA COVERAGE

Il nostro articolo è su Nature Communications! Siamo felici di aver contribuito a questo ambizioso progetto internazionale sugli ormoni steroidei nello sviluppo del cancro!

Signal transduction by receptor tyrosine kinases (RTKs) and nuclear receptors for steroid hormones is essential for body homeostasis, but the cross-talk between these receptor families is poorly understood. We observed that glucocorticoids inhibit signalling downstream of ​EGFR, an RTK. The underlying mechanism entails suppression of ​EGFR’s positive feedback loops and simultaneous triggering of negative feedback loops that normally restrain ​EGFR. Our studies in mice reveal that the regulation of ​EGFR’s feedback loops by glucocorticoids translates to circadian control of ​EGFR signalling: ​EGFR signals are suppressed by high glucocorticoids during the active phase (night-time in rodents), while ​EGFR signals are enhanced during the resting phase. Consistent with this pattern, treatment of animals bearing ​EGFR-driven tumours with a specific kinase inhibitor was more effective if administered during the resting phase of the day, when glucocorticoids are low. These findings support a circadian clock-based paradigm in cancer therapy.

Vai all’articolo originale (in inglese): Mattia Lauriola, Yehoshua Enuka, Amit Zeisel, Gabriele D’Uva, Lee Roth, Michal Sharon-Sevilla, Moshit Lindzen, Kirti Sharma, Nava Nevo, Morris Feldman, Silvia Carvalho, Hadas Cohen-Dvashi, Merav Kedmi, Nir Ben-Chetrit, Alon Chen, Rossella Solmi, Stefan Wiemann, Fernando Schmitt, Eytan Domany & Yosef Yarden. Diurnal suppression of ​EGFR signalling by glucocorticoids and implications for tumour progression and treatment. Nature Communications, 2015

 

MEDIA COVERAGE

06.10.2014 – Science Daily Tumors might grow faster at nigh


06.10.2014 – NATURE WORLD NEWS: Is Cancer Growth Nocturnal?


06.10.2014 – Softpedia: Cancer Tumors Appear to Grow Faster and Spread More Easily at Night


06.10.2014 – Medical Xpress: Tumors might grow faster at night: Hormone that keeps us alert also suppresses the spread of cancer


06.10.2014 – Senior Journal: Cancer Grows at Night, Maybe That’s When to Attack, New Study Says


07.10.2014 – Daily Mail: Cancerous tumours ‘grow faster at night’ – and drugs to fight the disease might work better during sleep, study finds


07.10.2014 – Counsel&Heal: Cancer Treatment More Efficient During Night Time:Study


07.10.2014 – Science 2.0: Cancer Might Grow Faster At Night


07.10.2014 – The Health Site: Revealed — cancer spreads during nights


07.10.2014 – bhataramedia: Tumor Dapat Tumbuh Lebih Cepat Di Malam Hari


07.10.2014 – Jews News: Israeli study: Tumors might grow more quickly at night


08.10.2014 – The Times of Israel: Tumors may grow faster at night, Israeli study shows


08.10.2014 – Journal de la Science: Les tumeurs grossiraient plus vite la nuit


08.10.2014 – Haaretz: Night time may be the right time to treat cancer, find Israeli scientists


09.10.2014 – Weizmann USA: Why Cancer Drugs May Work Better While You Sleep


09.10.2014 – Nature子刊:夜间癌细胞扩散的更快?


09.10.2014 – TIME: Why Cancer Drugs May Work Better While You Sleep


09-10-2014 – Medisite: CANCER : LES MÉDICAMENTS PLUS EFFICACES LA NUIT


10.10.2014 – TopSante: Cancer : les tumeurs se développent plus vite la nuit


10.10.2014 – Forbes: Cancer May Grow Faster While We Sleep


10.10.2014 – Jerusalem Post Tumors may grow faster at night, say Weizmann scientists


10.10.2014 – Medcenter: Una hormona que nos mantiene alerta también suprime la diseminación del cáncer


16.10.2014 – EACR (European Association for Cancer Research): TUMOURS MIGHT GROW FASTER AT NIGHT


16.10.2014 – Revista Genetica Medica: Ritmos circadianos y tratamiento contra el cáncer


17.10.2014 – University Herald: Hormone Active During Day Supresses Growth of Cancer Cells, Study


20.10.2014 – Stato Quotidiano: Ricercatrice Manfredonia: “tumori crescono più in fretta di notte”


24.10.2014 – Huffington Post: Does Cancer Grow More Aggressively at Night?

La nostra ricerca su meccanismi post-trascrizionali in cellule staminali tumorali è stata pubblicata!

Hypoxia has been long-time acknowledged as major cancer-promoting microenvironment. In such an energy-restrictive condition, post-transcriptional mechanisms gain importance over the energy-expensive gene transcription machinery. Here we show that the onset of hypoxia-induced cancer stem cell features requires the beta-catenin-dependent post-transcriptional up-regulation of CA9 and SNAI2 gene expression. In response to hypoxia, beta-catenin moves from the plasma membrane to the cytoplasm where it binds and stabilizes SNAI2 and CA9 mRNAs, in cooperation with the mRNA stabilizing protein HuR. We also provide evidence that the post-transcriptional activity of cytoplasmic beta-catenin operates under normoxia in basal-like/triple-negative breast cancer cells, where the beta-catenin knockdown suppresses the stem cell phenotype in vitro and tumor growth in vivo. In such cells, we unravel the generalized involvement of the beta-catenin-driven machinery in the stabilization of EGF-induced mRNAs, including the cancer stem cell regulator IL6. Our study highlights the crucial role of post-transcriptional mechanisms in the maintenance/acquisition of cancer stem cell features and suggests that the hindrance of cytoplasmic beta-catenin function may represent an unprecedented strategy for targeting breast cancer stem/basal-like cells.

Vai all’articolo originale (in inglese): Gabriele D’Uva*, Sara Bertoni, Mattia Lauriola, Sabrina De Carolis, Annalisa Pacilli, Laura D’Anello, Donatella Santini, Mario Taffurelli, Claudio Ceccarelli, Yosef Yarden, Lorenzo Montanaro, Massimiliano Bonafé, Gianluca Storci. Beta-Catenin/HuR Post-Transcriptional Machinery Governs Cancer Stem Cell Features in Response to Hypoxia. PloS One, 2013 (co-corresponding author)

La nostra ricerca su ormoni steroidei e cellule staminali ematopoietiche è stata pubblicata su Leukemia!

The role of corticosterone (Cort), the immune system’s major stress hormone, in the regulation of hematopoietic stem and progenitor cells (HSPCs) and their dynamic bone marrow (BM) microenvironment is currently unknown. We report that corticotropin-releasing factor receptor 1 (CRFR1) mutant mice with chronically low Cort levels showed aberrant HSPC regulation, having higher HSPC numbers and upregulation of the chemokine CXCL12, phenotypes that were restored by Cort supplementation. Expanded stromal progenitors known to support HSPCs were also observed in these low-Cort-containing mice. A similar phenotype was induced in wild-type (WT) mice by Metyrapone, a Cort synthesis inhibitor. Conversely, high Cort exposure induced HSPC apoptosis, reduced long-term BM repopulation and decreased stromal progenitor cell numbers. We documented circadian oscillations of Cort in WT BM but not in CRFR1 mutant mice, leading to diminished circadian BM CXCL12 fluctuations and increased number of circulating HSPCs in these mice. Finally, low Cort induced expansion of stromal progenitors, CXCL12 expression, HSPC proliferation and BM repopulation capacity, involving Notch1 signaling. This was associated with upregulation of the Notch ligand, Jagged1, in BM myeloid cells. Our results suggest that daily physiologic Cort oscillations are critical for balanced HSPC proliferation and function involving Notch1 signaling and their supportive BM microenvironment.

Vai all’articolo originale (in inglese): O Kollet*, Y Vagima*, G D’Uva, K Golan, J Canaani, T Itkin, S Gur-Cohen, A Kalinkovich, G Caglio, C Medaglia, A Ludin, K Lapid, E Shezen, A Neufeld-Cohen, D Varol, A Chen, T Lapidot. Physiologic corticosterone oscillations regulate murine hematopoietic stem/progenitor cell proliferation and CXCL12 expression by bone marrow stromal progenitorsLeukemia, 2013 (* equal contribution)