Sabrina De Carolis
University of Bologna
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Publication
Featured researches published by Sabrina De Carolis.
Journal of Cellular Physiology | 2014
Alessio Papi; Sabrina De Carolis; Sara Bertoni; Gianluca Storci; Virginia Sceberras; Donatella Santini; Claudio Ceccarelli; Mario Taffurelli; Marina Orlandi; Massimiliano Bonafè
Cancer stem cells (CSCs) are affected by the local micro‐environment, the niche, in which inflammatory stimuli and hypoxia act as steering factors. Here, two nuclear receptors (NRs) agonists, i.e. pioglitazone (PGZ), a ligand of peroxisome proliferator activated receptor‐γ, and 6‐OH‐11‐O‐hydroxyphenanthrene (IIF), a ligand of retinoid X receptors, were investigated for their capability to interference with the cross‐talk between breast CSCs and the niche compartment. We found that IIF potentiates the ability of PGZ to hamper the mammospheres‐forming capability of human breast tumours and MCF7 cancer cells, reducing the expression of CSCs regulatory genes (Notch3, Jagged1, SLUG, Interleukin‐6, Apolipoprotein E, Hypoxia inducible factor‐1α and Carbonic anhydrase IX). Notably, these effects are not observed in normal‐MS obtained from human breast tissue. Importantly, NRs agonists abolish the capability of hypoxic MCF7 derived exosomes to induce a pro‐inflammatory phenotype in mammary glands fibroblasts. Moreover, NRs agonist also directly acts on breast tumour associated fibroblasts to downregulate nuclear factor‐κB pathway and metalloproteinases (MMP2 and MMP9) expression and activity. In conclusion, NRs agonists disrupt the inflammatory cross‐talk of the hypoxic breast CSCs niche. J. Cell. Physiol. 229: 1595–1606, 2014.
PLOS ONE | 2013
Alessio Papi; Gianluca Storci; Tiziana Guarnieri; Sabrina De Carolis; Sara Bertoni; Nicola Avenia; Alessandro Sanguinetti; Angelo Sidoni; Donatella Santini; Claudio Ceccarelli; Mario Taffurelli; Marina Orlandi; Massimiliano Bonafè
Aims Cancer stem cell biology is tightly connected to the regulation of the pro-inflammatory cytokine network. The concept of cancer stem cells “inflammatory addiction” leads to envisage the potential role of anti-inflammatory molecules as new anti-cancer targets. Here we report on the relationship between nuclear receptors activity and the modulation of the pro-inflammatory phenotype in breast cancer stem cells. Methods Breast cancer stem cells were expanded as mammospheres from normal and tumor human breast tissues and from tumorigenic (MCF7) and non tumorigenic (MCF10) human breast cell lines. Mammospheres were exposed to the supernatant of breast tumor and normal mammary gland tissue fibroblasts. Results In mammospheres exposed to the breast tumor fibroblasts supernatant, autocrine tumor necrosis factor-α signalling engenders the functional interplay between peroxisome proliferator activated receptor-α and hypoxia inducible factor-1α (PPARα/HIF1α). The two proteins promote mammospheres formation and enhance each other expression via miRNA130b/miRNA17-5p-dependent mechanism which is antagonized by PPARγ. Further, the PPARα/HIF1α interplay regulates the expression of the pro-inflammatory cytokine interleukin-6, the hypoxia survival factor carbonic anhydrase IX and the plasma lipid carrier apolipoprotein E. Conclusion Our data demonstrate the importance of exploring the role of nuclear receptors (PPARα/PPARγ) in the regulation of pro-inflammatory pathways, with the aim to thwart breast cancer stem cells functioning.
PLOS ONE | 2013
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 Bonafè; Gianluca Storci
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.
Cancer Research | 2017
Pasquale Sansone; Marjan Berishaj; Vinagolu K. Rajasekhar; Claudio Ceccarelli; Qing Chang; Antonio Strillacci; Claudia Savini; Lauren Shapiro; Robert L. Bowman; Chiara Mastroleo; Sabrina De Carolis; Laura Daly; Alberto Benito-Martin; Fabiana Perna; Nicola Fabbri; John H. Healey; Enzo Spisni; Monica Cricca; David Lyden; Massimiliano Bonafè; Jacqueline Bromberg
The hypothesis that microvesicle-mediated miRNA transfer converts noncancer stem cells into cancer stem cells (CSC) leading to therapy resistance remains poorly investigated. Here we provide direct evidence supporting this hypothesis, by demonstrating how microvesicles derived from cancer-associated fibroblasts (CAF) transfer miR-221 to promote hormonal therapy resistance (HTR) in models of luminal breast cancer. We determined that CAF-derived microvesicles horizontally transferred miR-221 to tumor cells and, in combination with hormone therapy, activated an ERlo/Notchhi feed-forward loop responsible for the generation of CD133hi CSCs. Importantly, microvesicles from patients with HTR metastatic disease expressed high levels of miR-221. We further determined that the IL6-pStat3 pathway promoted the biogenesis of onco-miR-221hi CAF microvesicles and established stromal CSC niches in experimental and patient-derived breast cancer models. Coinjection of patient-derived CAFs from bone metastases led to de novo HTR tumors, which was reversed with IL6R blockade. Finally, we generated patient-derived xenograft (PDX) models from patient-derived HTR bone metastases and analyzed tumor cells, stroma, and microvesicles. Murine and human CAFs were enriched in HTR tumors expressing high levels of CD133hi cells. Depletion of murine CAFs from PDX restored sensitivity to HT, with a concurrent reduction of CD133hi CSCs. Conversely, in models of CD133neg, HT-sensitive cancer cells, both murine and human CAFs promoted de novo HT resistance via the generation of CD133hi CSCs that expressed low levels of estrogen receptor alpha. Overall, our results illuminate how microvesicle-mediated horizontal transfer of genetic material from host stromal cells to cancer cells triggers the evolution of therapy-resistant metastases, with potentially broad implications for their control. Cancer Res; 77(8); 1927-41. ©2017 AACR.
Haematologica | 2014
Francesca Bonifazi; Gianluca Storci; Giuseppe Bandini; Elena Marasco; Elisa Dan; Elena Zani; Fiorenzo Albani; Sara Bertoni; Andrea Bontadini; Sabrina De Carolis; Maria Rosaria Sapienza; Simonetta Rizzi; Maria Rosa Motta; Martina Ferioli; Paolo Garagnani; Michele Cavo; Vilma Mantovani; Massimiliano Bonafè
Busulfan liver metabolism depends on glutathione, a crucial mediator of cellular and systemic stress. Here we investigated 40 polymorphisms at 27 loci involved in hepatic glutathione homeostasis, with the aim of testing their impact on the clinical outcome of 185 busulfan-conditioned allogeneic transplants. GSTA2 S112T serine allele homozygosity is an independent prognostic factor for poorer survival (RR=2.388), for increased any time- and 100-day transplant-related mortality (RR=4.912 and RR=5.185, respectively). The genotype also predicts a wider busulfan area under the concentration-time curve (1214.36±570.06 vs. 838.10±282.40 mMol*min) and higher post-transplant bilirubin serum levels (3.280±0.422 vs. 1.874+0.197 mg/dL). In vitro, busulfan elicits pro-inflammatory activation (increased NF-KappaB activity and interleukin-8 expression) in human hepatoma cells. At the same time, the drug down-regulates a variety of genes involved in bilirubin liver clearance: constitutive androstane receptor, multidrug resistance-associated protein, solute carrier organic anion transporters, and even GSTA2. It is worthy of note that GSTA2 also acts as an intra-hepatic bilirubin binding protein. These data underline the prognostic value of GSTA2 genetic variability in busulfan-conditioned allotransplants and suggest a patho-physiological model in which busulfan-induced inflammation leads to the impairment of post-transplant bilirubin metabolism.
Mechanisms of Ageing and Development | 2017
Francesco Prattichizzo; Luigina Micolucci; Monica Cricca; Sabrina De Carolis; Emanuela Mensà; Antonio Ceriello; Antonio Procopio; Massimiliano Bonafè; Fabiola Olivieri
Exosomes are nanovesicles formed by inward budding of endosomal membranes. They exert complex immunomodulatory effects on target cells, acting both as antigen-presenting vesicles and as shuttles for packets of information such as proteins, coding and non-coding RNA, and nuclear and mitochondrial DNA fragments. Albeit different, all such functions seem to be encompassed in the adaptive mechanism mediating the complex interactions of the organism with a variety of stressors, providing both for defense and for the evolution of symbiotic relationships with others organisms (gut microbiota, bacteria, and viruses). Intriguingly, the newly deciphered human virome and exosome biogenesis seem to share some physical-chemical characteristics and molecular mechanisms. Exosomes are involved in immune system recognition of self from non-self throughout life: they are therefore ideal candidate to modulate inflamm-aging, the chronic, systemic, age-related pro-inflammatory status, which influence the development/progression of the most common age-related diseases (ARDs). Not surprisingly, recent evidence has documented exosomal alteration during aging and in association with ARDs, even though data in this field are still limited. Here, we review current knowledge on exosome-based trafficking between immune cells and self/non-self cells (i.e. the virome), sketching a nano-perspective on inflamm-aging and on the mechanisms involved in health maintenance throughout life.
Journal of Cellular Physiology | 2016
Sabrina De Carolis; Sara Bertoni; Marina Nati; Laura D'Anello; Alessio Papi; Anna Tesei; Monica Cricca; Massimiliano Bonafè
The hypoxic environment is a crucial component of the cancer stem cell niche and it is capable of eliciting stem cell features in cancer cells. We previously reported that SNAI2 up‐regulates the expression of Carbonic Anhydrase iso‐enzyme 9 (CA9) in hypoxic MCF7 cells. Here we show that SNAI2 down‐regulates miR34a expression in hypoxic MCF7 cell‐derived mammospheres. Next, we report on the capability of miR34a to decrease CA9 mRNA stability and CA9 protein expression. We also convey that the over‐expression of cloned CA9‐mRNA‐3′UTR increases the mRNA half‐life and protein levels of two miR34a targets JAGGED1 and NOTCH3. The data here reported shows that the SNAI2‐dependent down‐regulation of miR34a substantially contributes to the post‐transcriptional up‐regulation of CA9, and that CA9‐mRNA‐3′UTR acts as an endogenous microRNA sponge. We conclude that CA9/miR34 interplay shares in the hypoxic regulation of mammospheres and therefore, may play a relevant role in the hypoxic breast cancer stem cell niche. J. Cell. Physiol. 231: 1534–1541, 2016.
American Journal of Pathology | 2013
Gianluca Storci; Sara Bertoni; Sabrina De Carolis; Alessio Papi; Marina Nati; Claudio Ceccarelli; Chiara Pirazzini; Paolo Garagnani; Alberto Ferrarini; Genny Buson; Massimo Delledonne; Michelangelo Fiorentino; Elisa Capizzi; Elisa Gruppioni; Mario Taffurelli; Donatella Santini; Claudio Franceschi; Giuseppe Bandini; Francesca Bonifazi; Massimiliano Bonafè
Cancer stem cell survival relies on the activation of inflammatory pathways, which is speculatively triggered by cell autonomous mechanisms or by microenvironmental stimuli. Here, we observed that hypoxic bone marrow stroma-derived transforming growth factor-β 1 promotes the growth of human breast cancer stem cells as mammospheres. The ensuing Slug-dependent serine 139 phosphorylation of the DNA damage sensor H2AX in breast cancer stem cells induces tumor necrosis factor-α and IL-8 mRNAs, whose stability is enhanced by cytoplasmic β-catenin. β-Catenin also up-regulates and binds miR-221, reducing the stability of the miR-221 targets Rad51 and ERα mRNAs. Our data show that the Slug/β-catenin-dependent activation of DNA damage signaling triggered by the hypoxic microenvironment sustains the proinflammatory phenotype of breast cancer stem cells.
Future Microbiology | 2018
Sabrina De Carolis; Alice Pellegrini; Donatella Santini; Claudio Ceccarelli; Antonio De Leo; Federica Alessandrini; Chiara Arienti; Sara Pignatta; Anna Tesei; Vilma Mantovani; Claudio Zamagni; Mario Taffurelli; Pasquale Sansone; Massimiliano Bonafè; Monica Cricca
AIM HPV DNA has never been investigated in nipple discharges (ND) and serum-derived extracellular vesicles, although its presence has been reported in ductal lavage fluids and blood specimens. MATERIALS & METHODS We analyzed 50 ND, 22 serum-derived extracellular vesicles as well as 51 pathologic breast tissues for the presence of 16 HPV DNA types. RESULTS We show that the presence of HPV DNA in the ND is predictive of HPV DNA-positive breast lesions and that HPV DNA is more represented in intraductal papillomas. We also show the presence of HPV DNA in the serum-derived extracellular vesicles. CONCLUSION Our data supports the use of liquid biopsy to detect HPV DNA in breast pathology.
Bone Marrow Transplantation | 2018
Francesca Bonifazi; Elisa Dan; Myriam Labopin; Mariarosaria Sessa; Viviana Guadagnuolo; Martina Ferioli; Simonetta Rizzi; Sabrina De Carolis; Barbara Sinigaglia; Maria Rosa Motta; Andrea Bontadini; Valeria Giudice; Giovanni Martinelli; Mario Arpinati; Michele Cavo; Massimiliano Bonafè; Gianluca Storci
Umbilical Cord Blood (UCB) represents a valid option for patients with hematopoietic malignancies lacking an HLA matched donor. To overcome the limitation of the low stem cell dose of UCB, the intrabone (IB) route has been proposed. We report the results of a prospective study on a poor-prognosis cohort of 23 patients receiving intrabone single UCB transplant (Clinicaltrials.gov NCT00886522). Cumulative incidence of hematological recovery at day 90 was 82 ± 9% (ANC > 0.5 × 109/L) and 70 ± 10% (platelet > 50 × 109/L) and correlated with CD34 + cells in the graft. NRM was 20 ± 9%. No severe aGVHD and only one extensive cGVHD occurred, with fast immune reconstitution. To test the hypothesis that the direct IB injection could affect the expression of stem cells regulatory pathways, CD34 + cells from BM aspirates at day + 10, + 20, + 30, processed in hypoxic conditions mimicking the BM-microenvironment (7%pO2), were studied for the expression of c-Mpl, Notch1 and CXCR4. We found that the expression of c-Mpl in CD34 + cells at day + 10 significantly correlated with hematological recovery. In conclusion, IB-UCB transplant success is associated with low incidence of GVHD and high-speed platelet recovery; intrabone route may preserve full hematopoietic stemness by direct delivery of UCB stem cells into the hypoxic HSC niche.