10 results on '"Mario Cioce"'
Search Results
2. Interrogating colorectal cancer metastasis to liver: a search for clinically viable compounds and mechanistic insights in colorectal cancer Patient Derived Organoids
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Mario Cioce, Maria Rita Fumagalli, Sara Donzelli, Frauke Goeman, Valeria Canu, Daniela Rutigliano, Giulia Orlandi, Andrea Sacconi, Claudio Pulito, Alina Catalina Palcau, Maurizio Fanciulli, Aldo Morrone, Maria Grazia Diodoro, Marco Caricato, Anna Crescenzi, Martina Verri, Vito Michele Fazio, Stefano Zapperi, Massimo Levrero, Sabrina Strano, Gian Luca Grazi, Caterina La Porta, and Giovanni Blandino
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CRC ,Liver metastases ,Pentoxifylline ,Dexketoprofen ,Desloratadine ,Organoids ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background Approximately 20–50% of patients presenting with localized colorectal cancer progress to stage IV metastatic disease (mCRC) following initial treatment and this is a major prognostic determinant. Here, we have interrogated a heterogeneous set of primary colorectal cancer (CRC), liver CRC metastases and adjacent liver tissue to identify molecular determinants of the colon to liver spreading. Screening Food and Drug Administration (FDA) approved drugs for their ability to interfere with an identified colon to liver metastasis signature may help filling an unmet therapeutic need. Methods RNA sequencing of primary colorectal cancer specimens vs adjacent liver tissue vs synchronous and asynchronous liver metastases. Pathways enrichment analyses. The Library of Integrated Network-based Cellular Signatures (LINCS)-based and Connectivity Map (CMAP)-mediated identification of FDA-approved compounds capable to interfere with a 22 gene signature from primary CRC and liver metastases. Testing the identified compounds on CRC-Patient Derived Organoid (PDO) cultures. Microscopy and Fluorescence Activated Cell Sorting (FACS) based analysis of the treated PDOs. Results We have found that liver metastases acquire features of the adjacent liver tissue while partially losing those of the primary tumors they derived from. We have identified a 22-gene signature differentially expressed among primary tumors and metastases and validated in public databases. A pharmacogenomic screening for FDA-approved compounds capable of interfering with this signature has been performed. We have validated some of the identified representative compounds in CRC-Patient Derived Organoid cultures (PDOs) and found that pentoxyfilline and, to a minor extent, dexketoprofen and desloratadine, can variably interfere with number, size and viability of the CRC –PDOs in a patient-specific way. We explored the pentoxifylline mechanism of action and found that pentoxifylline treatment attenuated the 5-FU elicited increase of ALDHhigh cells by attenuating the IL-6 mediated STAT3 (tyr705) phosphorylation. Conclusions Pentoxifylline synergizes with 5-Fluorouracil (5-FU) in attenuating organoid formation. It does so by interfering with an IL-6-STAT3 axis leading to the emergence of chemoresistant ALDHhigh cell subpopulations in 5-FU treated PDOs. A larger cohort of CRC-PDOs will be required to validate and expand on the findings of this proof-of-concept study.
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- 2023
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3. Mesothelioma-Associated Fibroblasts Modulate the Response of Mesothelioma Patient-Derived Organoids to Chemotherapy via Interleukin-6
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Mario Cioce, Veronica Gatti, Fabiana Napolitano, Noemi Maria Giorgiano, Andrea Marra, Giuseppe Portella, Alfonso Fiorelli, Francesca Pentimalli, and Vito Michele Fazio
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mesothelioma patient-derived organoids ,PDO ,IL-6 ,mesothelioma-associated fibroblasts ,cocultures ,cisplatin ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Malignant pleural mesothelioma (MPM) remains an incurable disease. This is partly due to the lack of experimental models that fully recapitulate the complexity and heterogeneity of MPM, a major challenge for therapeutic management of the disease. In addition, the contribution of the MPM microenvironment is relevant for the adaptive response to therapy. We established mesothelioma patient-derived organoid (mPDO) cultures from MPM pleural effusions and tested their response to pemetrexed and cisplatin. We aimed to evaluate the contribution of mesothelioma-associated fibroblasts (MAFs) to the response to pemetrexed and cisplatin (P+C). Organoid cultures were obtained from eight MPM patients using specific growth media and conditions to expand pleural effusion-derived cells. Flow cytometry was used to verify the similarity of the organoid cultures to the original samples. MAFs were isolated and co-cultured with mPDOs, and the addition of MAFs reduced the sensitivity of mPDOs to P+C. Organoid formation and expression of cancer stem cell markers such as ABCG2, NANOG, and CD44 were altered by conditioned media from treated MAFs. We identified IL-6 as the major contributor to the attenuated response to chemotherapy. IL-6 secretion by MAFs is correlated with increased resistance of mPDOs to pemetrexed and cisplatin.
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- 2024
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4. A PIK3CA-mutant breast cancer metastatic patient-derived organoid approach to evaluate alpelisib treatment for multiple secondary lesions
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Sara Donzelli, Mario Cioce, Andrea Sacconi, Francesca Zanconato, Theodora Daralioti, Frauke Goeman, Giulia Orlandi, Simona Di Martino, Vito Michele Fazio, Gabriele Alessandrini, Stefano Telera, Mariantonia Carosi, Gennaro Ciliberto, Claudio Botti, Sabrina Strano, Stefano Piccolo, and Giovanni Blandino
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Breast cancer metastases ,Organoids ,Alpelisib ,PIK3CA mutations ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Published
- 2022
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5. Breast cancer metastasis: Is it a matter of OMICS and proper ex-vivo models?
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Mario Cioce, Andrea Sacconi, Sara Donzelli, Claudia Bonomo, Letizia Perracchio, Mariantonia Carosi, Stefano Telera, Vito Michele Fazio, Claudio Botti, Sabrina Strano, and Giovanni Blandino
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Metastatic breast cancer ,Organoids ,PDTO ,Genomic ,Proteomic ,multi-OMICS ,Biotechnology ,TP248.13-248.65 - Abstract
Genomics has greatly increased the understanding of the study of breast cancer (BC) and has shaped the concept of intra-tumor heterogeneity, currently recognized as a propelling force for cancer progression. In this context, knowledge and understanding of metastatic breast cancer (mBC) has somehow lagged behind that of primary breast cancer. This may be explained by the relative scarcity of matched mBC samples, however it is possible that the mutation spectrum obtained from primary BC does not capture the full complexity of the metastatic disease. Here, we provide a few examples supporting this possibility, from public databases. We evoke the need to perform an integrated multi-OMICS characterization of mBC, to obtain a broad understanding of this complex disease, whose evolution cannot be explained solely by genomics. Pertinent to this, we suggest that rather an infrequent use of Patient-Derived –Tumor-Organoids (PDTOs) may be influenced by assuming that the metastatic conditions of PDTOs growth (mPDTOs) should be similar to those of the tissue of origin. We challenge this view by suggesting that the use of “target-organ inspired” growth conditions for mPDTOs, may better fit the emerging knowledge of metastatic disease. Thus, the integrated use of multi-OMICS and of clinically relevant mPDTOs may allow a further understanding of such disease and foster therapeutically relevant advances. We believe that our points may be valid for other solid cancers.
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- 2022
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6. Arachidonic acid drives adaptive responses to chemotherapy-induced stress in malignant mesothelioma
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Mario Cioce, Claudia Canino, Harvey Pass, Giovanni Blandino, Sabrina Strano, and Vito Michele Fazio
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Arachidonic acid ,cPLA2 ,NFkB ,Chemoresistance ,ALDH ,Spheroids ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background High resistance to therapy and poor prognosis characterizes malignant pleural mesothelioma (MPM). In fact, the current lines of treatment, based on platinum and pemetrexed, have limited impact on the survival of MPM patients. Adaptive response to therapy-induced stress involves complex rearrangements of the MPM secretome, mediated by the acquisition of a senescence-associated-secretory-phenotype (SASP). This fuels the emergence of chemoresistant cell subpopulations, with specific gene expression traits and protumorigenic features. The SASP-driven rearrangement of MPM secretome takes days to weeks to occur. Thus, we have searched for early mediators of such adaptive process and focused on metabolites differentially released in mesothelioma vs mesothelial cell culture media, after treatment with pemetrexed. Methods Mass spectrometry-based (LC/MS and GC/MS) identification of extracellular metabolites and unbiased statistical analysis were performed on the spent media of mesothelial and mesothelioma cell lines, at steady state and after a pulse with pharmacologically relevant doses of the drug. ELISA based evaluation of arachidonic acid (AA) levels and enzyme inhibition assays were used to explore the role of cPLA2 in AA release and that of LOX/COX-mediated processing of AA. QRT-PCR, flow cytometry analysis of ALDH expressing cells and 3D spheroid growth assays were employed to assess the role of AA at mediating chemoresistance features of MPM. ELISA based detection of p65 and IkBalpha were used to interrogate the NFkB pathway activation in AA-treated cells. Results We first validated what is known or expected from the mechanism of action of the antifolate. Further, we found increased levels of PUFAs and, more specifically, arachidonic acid (AA), in the transformed cell lines treated with pemetrexed. We showed that pharmacologically relevant doses of AA tightly recapitulated the rearrangement of cell subpopulations and the gene expression changes happening in pemetrexed -treated cultures and related to chemoresistance. Further, we showed that release of AA following pemetrexed treatment was due to cPLA2 and that AA signaling impinged on NFkB activation and largely affected anchorage-independent, 3D growth and the resistance of the MPM 3D cultures to the drug. Conclusions AA is an early mediator of the adaptive response to pem in chemoresistant MPM and, possibly, other malignancies.
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- 2021
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7. Mapping Non-Coding RNAs in Space and Time: Another Weapon to Dissect Intra-Tumor Heterogeneity in Cancer Progression
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Mario Cioce, Andrea Marra, Daniela Rutigliano, and Vito Michele Fazio
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n/a ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
It is increasingly clear that Intratumor heterogeneity (ITH) fuels tumor evolution, matching the concept of cancer as a heterogeneous ecosystem of spatially and temporally modulated cell subpopulations, which exploits dynamic strategies to hijack local and systemic resources and tissue(s) space [...]
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- 2023
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8. Insights into Intra-Tumoral Heterogeneity: Transcriptional Profiling of Chemoresistant MPM Cell Subpopulations Reveals Involvement of NFkB and DNA Repair Pathways and Contributes a Prognostic Signature
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Mario Cioce, Andrea Sacconi, Harvey I. Pass, Claudia Canino, Sabrina Strano, Giovanni Blandino, and Vito Michele Fazio
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chemoresistance ,ALDH ,gene expression ,NFkB ,DNA repair ,butein ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Chemoresistance is a hallmark of malignant pleural mesothelioma (MPM) management and the expression of ALDH1A3 is responsible for the survival and activity of MPM chemoresistant cell subpopulations (ALDHbright cells). We enriched mesothelioma ALDHbright cells to near homogeneity by FACS sorting and an Aldefluor assay and performed unbiased Affymetrix gene expression profiling. Viability and ELISA assays were used to rule out significant apoptosis in the sorted cell subpopulations and to assess target engagement by butein. Statistical analysis of the results, pathway enrichment and promoter enrichment were employed for the generation of the data. Q-RTPCR was used to validate a subset of the identified, modulated mRNAs In this work, we started from the observation that the mRNA levels of the ALDH1A3 isoform could prognostically stratify MPM patients. Thus, we purified MPM ALDHbright cells from NCI-H2595 cells and interrogated their gene expression (GES) profile. We analyzed the GES of the purified cells at both a steady state and upon treatment with butein (a multifunctional tetrahydroxy-chalcone), which abates the ALDHbright cell number, thereby exerting chemo-sensitizing effects in vitro and in vivo. We identified 924 genes modulated in a statistically significant manner as a function of ALDH status and of the response to the inhibitor. Pathway and promoter enrichment identified the molecular determinant of high ALDH status and how butein treatment altered the molecular portrait of those chemoresistant cell subpopulations. Further, we unraveled an eighteen-gene signature with high prognostic significance for MPM patients, and showed that most of the identified prognostic contributors escaped the analysis of unfractionated samples. This work proves that digging into the unexplored field of intra-tumor heterogeneity (ITH) by working at the cell subpopulation level may provide findings of prognostic relevance, in addition to mechanistic insights into tumor resistance to therapy.
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- 2021
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9. EphA2 and EGFR: Friends in Life, Partners in Crime. Can EphA2 Be a Predictive Biomarker of Response to Anti-EGFR Agents?
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Mario Cioce and Vito Michele Fazio
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EphA2 ,EGFR ,TKI ,ephrins ,CRC ,CSCs ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
The Eph receptors represent the largest group among Receptor Tyrosine kinase (RTK) families. The Eph/ephrin signaling axis plays center stage during development, and the deep perturbation of signaling consequent to its dysregulation in cancer reveals the multiplicity and complexity underlying its function. In the last decades, they have emerged as key players in solid tumors, including colorectal cancer (CRC); however, what causes EphA2 to switch between tumor-suppressive and tumor-promoting function is still an active theater of investigation. This review summarizes the recent advances in understanding EphA2 function in cancer, with detail on the molecular determinants of the oncogene-tumor suppressor switch function of EphA2. We describe tumor context-specific examples of EphA2 signaling and the emerging role EphA2 plays in supporting cancer—stem—cell-like populations and overcoming therapy-induced stress. In such a frame, we detail the interaction of the EphA2 and EGFR pathway in solid tumors, including colorectal cancer. We discuss the contribution of the EphA2 oncogenic signaling to the resistance to EGFR blocking agents, including cetuximab and TKIs.
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- 2021
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10. Establishing Primary Malignant Pleural Mesothelioma (MPM) Cell Cultures
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Mario Cioce, Claudia Canino, Sabrina Strano, and Giovanni Blandino
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Biology (General) ,QH301-705.5 - Abstract
This is a general protocol for the isolation and maintenance of primary MPM cultures as a tool for the identification of Tumor Initiating Cells and early progenitor-targeting drugs (Cioce et al., 2010). Primary cultures can be propagated efficiently for 8-12 weeks and xenotransplanted in NOD/SCID mice while retaining the histofeatures of the originating tumor (Canino et al., 2012). The protocol is suitable for both MPM solid specimens and pleural effusion. For increased clarity, initially two separate sections addressing the isolation of MPM cells from solid tumors and pleural effusions are here provided.
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- 2012
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