3 results on '"Savini, Claudia"'
Search Results
2. Evolution of Cancer Stem-like Cells in Endocrine-Resistant Metastatic Breast Cancers Is Mediated by Stromal Microvesicles
- Author
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Alberto Benito-Martin, Antonio Strillacci, David Lyden, Claudia Savini, Pasquale Sansone, Sabrina De Carolis, John H. Healey, Enzo Spisni, Robert L. Bowman, Qing Chang, Vinagolu K. Rajasekhar, Chiara Mastroleo, Marjan Berishaj, Fabiana Perna, Massimiliano Bonafè, Laura Daly, Nicola Fabbri, Monica Cricca, Claudio Ceccarelli, Jacqueline Bromberg, Lauren Q. Shapiro, Sansone, Pasquale, Berishaj, Marjan, Rajasekhar, Vinagolu K, Ceccarelli, Claudio, Chang, Qing, Strillacci, Antonio, Savini, Claudia, Shapiro, Lauren, Bowman, Robert, Mastroleo, Chiara, De Carolis, Sabrina, Daly, Laura, Benito-Martin, Alberto, Perna, Fabiana, Fabbri, Nicola, Healey, John H, Spisni, Enzo, Cricca, Monica, Lyden, David, Bonafé, Massimiliano, and Bromberg, Jacqueline
- Subjects
STAT3 Transcription Factor ,0301 basic medicine ,Cancer Research ,Pathology ,medicine.medical_specialty ,Neoplasms, Hormone-Dependent ,Stromal cell ,Antineoplastic Agents, Hormonal ,Breast Neoplasms ,Mice, SCID ,Biology ,Article ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Breast cancer ,Cancer-Associated Fibroblasts ,Cell-Derived Microparticles ,Mice, Inbred NOD ,Cancer stem cell ,medicine ,Animals ,Humans ,breast cancer, stromal microvesicles, endocrine resistant metastatic breast cancer ,Fulvestrant ,Estradiol ,Interleukin-6 ,Cancer ,medicine.disease ,Microvesicles ,MicroRNAs ,030104 developmental biology ,Oncology ,Drug Resistance, Neoplasm ,Case-Control Studies ,030220 oncology & carcinogenesis ,Cancer cell ,MCF-7 Cells ,Neoplastic Stem Cells ,Cancer research ,Heterografts ,Hormonal therapy ,Female ,Stromal Cells ,Stem cell ,HeLa Cells - Abstract
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.
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- 2017
3. Packaging and transfer of mitochondrial DNA via exosomes regulate escape from dormancy in hormonal therapy-resistant breast cancer
- Author
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Claudia Savini, Laura Benedetta Amato, Basant Kumar Thakur, Jacqueline Bromberg, Giuseppe Gasparre, Chiara Mastroleo, Monica Cricca, Ivana Kurelac, Qing Chang, Massimiliano Bonafè, Kunihiro Uryu, Alexander Galkin, Anna Stepanova, Pasquale Sansone, Larry Norton, Nadine Soplop, David Lyden, Luisa Iommarini, Ayuko Hoshino, Laura Daly, Antonio Strillacci, Sansone, Pasquale, Savini, Claudia, Kurelac, Ivana, Chang, Qing, Amato, LAURA BENEDETTA, Strillacci, Antonio, Stepanova, Anna, Iommarini, Luisa, Mastroleo, Chiara, Daly, Laura, Galkin, Alexander, Thakur, Basant Kumar, Soplop, Nadine, Uryu, Kunihiro, Hoshinob, Ayuko, Norton, Larry, Bonafe', Massimiliano, Cricca, Monica, Gasparre, Giuseppe, Lyden, David, and Bromberg, Jacqueline
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0301 basic medicine ,Mitochondrial DNA ,exosomes, mitochondrial DNA, cancer stem cells, hormonal therapy, metastasis ,Gene Transfer, Horizontal ,Medizin ,Breast Neoplasms ,Biology ,Exosomes ,DNA, Mitochondrial ,Corrections ,Oxidative Phosphorylation ,Metastasis ,03 medical and health sciences ,Breast cancer ,Cancer stem cell ,Cell Line, Tumor ,medicine ,Humans ,Multidisciplinary ,Cancer ,NADH Dehydrogenase ,Fibroblasts ,medicine.disease ,Phenotype ,Xenograft Model Antitumor Assays ,Microvesicles ,3. Good health ,030104 developmental biology ,Receptors, Estrogen ,Drug Resistance, Neoplasm ,Immunology ,Genome, Mitochondrial ,Cancer research ,MCF-7 Cells ,Hormonal therapy ,Female - Abstract
The horizontal transfer of mtDNA and its role in mediating resistance to therapy and an exit from dormancy have never been investigated. Here we identified the full mitochondrial genome in circulating extracellular vesicles (EVs) from patients with hormonal therapy-resistant (HTR) metastatic breast cancer. We generated xenograft models of HTR metastatic disease characterized by EVs in the peripheral circulation containing mtDNA. Moreover, these human HTR cells had acquired host-derived (murine) mtDNA promoting estrogen receptor-independent oxidative phosphorylation (OXPHOS). Functional studies identified cancer-associated fibroblast (CAF)-derived EVs (from patients and xenograft models) laden with whole genomic mtDNA as a mediator of this phenotype. Specifically, the treatment of hormone therapy (HT)-naive cells or HT-treated metabolically dormant populations with CAF-derived mtDNAhi EVs promoted an escape from metabolic quiescence and HTR disease both in vitro and in vivo. Moreover, this phenotype was associated with the acquisition of EV mtDNA, especially in cancer stem-like cells, expression of EV mtRNA, and restoration of OXPHOS. In summary, we have demonstrated that the horizontal transfer of mtDNA from EVs acts as an oncogenic signal promoting an exit from dormancy of therapy-induced cancer stem-like cells and leading to endocrine therapy resistance in OXPHOS-dependent breast cancer.
- Published
- 2017
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