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6 results on '"Sara Picinoli"'

1. Novel cellular systems unveil mucosal melanoma initiating cells and a role for PI3K/Akt/mTOR pathway in mucosal melanoma fitness

Author

Matilde Monti, Luisa Benerini Gatta, Mattia Bugatti, Irene Pezzali, Sara Picinoli, Marcello Manfredi, Antonio Lavazza, Virginia Vita Vanella, Veronica De Giorgis, Lucia Zanatta, Francesco Missale, Silvia Lonardi, Benedetta Zanetti, Giovanni Bozzoni, Moris Cadei, Andrea Abate, Barbara Vergani, Piera Balzarini, Simonetta Battocchio, Carla Facco, Mario Turri-Zanoni, Paolo Castelnuovo, Piero Nicolai, Ester Fonsatti, Biagio Eugenio Leone, Emilio Marengo, Sandra Sigala, Roberto Ronca, Michela Perego, Davide Lombardi, and William Vermi

Subjects
Mucosal melanomas, Cell lines, Melanoma stem cells, MITF, PI3K/AKT/mTOR, Medicine
Abstract

Abstract Background Mucosal Melanomas (MM) are highly aggressive neoplasms arising from mucosal melanocytes. Current treatments offer a limited survival benefit for patients with advanced MM; moreover, the lack of pre-clinical cellular systems has significantly limited the understanding of their immunobiology. Methods Five novel cell lines were obtained from patient-derived biopsies of MM arising in the sino-nasal mucosa and designated as SN-MM1-5. The morphology, ultrastructure and melanocytic identity of SN-MM cell lines were validated by transmission electron microscopy and immunohistochemistry. Moreover, in vivo tumorigenicity of SN-MM1-5 was tested by subcutaneous injection in NOD/SCID mice. Molecular characterization of SN-MM cell lines was performed by a mass-spectrometry proteomic approach, and their sensitivity to PI3K chemical inhibitor LY294002 was validated by Akt activation, measured by pAkt(Ser473) and pAkt(Thr308) in immunoblots, and MTS assay. Results This study reports the validation and functional characterization of five newly generated SN-MM cell lines. Compared to the normal counterpart, the proteomic profile of SN-MM is consistent with transformed melanocytes showing a heterogeneous degree of melanocytic differentiation and activation of cancer-related pathways. All SN-MM cell lines resulted tumorigenic in vivo and display recurrent structural variants according to aCGH analysis. Of relevance, the microscopic analysis of the corresponding xenotransplants allowed the identification of clusters of MITF-/CDH1-/CDH2 + /ZEB1 + /CD271 + cells, supporting the existence of melanoma-initiating cells also in MM, as confirmed in clinical samples. In vitro, SN-MM cell lines were sensitive to cisplatin, but not to temozolomide. Moreover, the proteomic analysis of SN-MM cell lines revealed that RICTOR, a subunit of mTORC2 complex, is the most significantly activated upstream regulator, suggesting a relevant role for the PI3K-Akt-mTOR pathway in these neoplasms. Consistently, phosphorylation of NDRG1 and Akt activation was observed in SN-MM, the latter being constitutive and sustained by PTEN loss in SN-MM2 and SN-MM3. The cell viability impairment induced by LY294002 confirmed a functional role for the PI3K-Akt-mTOR pathway in SN-MM cell lines. Conclusions Overall, these novel and unique cellular systems represent relevant experimental tools for a better understanding of the biology of these neoplasms and, as an extension, to MM from other sites.

Published
2024
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2. Data from A Population of TIM4+FOLR2+ Macrophages Localized in Tertiary Lymphoid Structures Correlates to an Active Immune Infiltrate Across Several Cancer Types

Author

William Vermi, Federica Benvenuti, Julie Helft, Yoann Missolo-Koussou, Nicoletta Caronni, Sara Picinoli, Irene Pezzali, Laura Ardighieri, Matilde Monti, Francesco Missale, Marco Bergamini, and Mattia Bugatti

Abstract

TIM4 has previously been associated with antitumor immunity, yet the pattern of expression and the function of this receptor across human cancer tissues remain poorly explored. Here we combined extensive immunolabeling of human tissues with in silico analysis of pan-cancer transcriptomic data sets to explore the clinical significance of TIM4 expression. Our results unveil that TIM4 is expressed on a fraction of cavity macrophages (CATIM4+MΦ) of carcinoma patients. Moreover, we uncover a high expression of TIM4 on macrophages of the T-cell zone of the carcinoma-associated tertiary lymphoid structures (TLSTIM4+MΦ). In silico analysis of a pan-cancer data set revealed a positive correlation between TIM4 expression and markers of B cells, effector CD8+ T cells, and a 12-chemokine signature defining tertiary lymphoid structure. In addition, TLSTIM4+MΦ were enriched in cancers displaying microsatellite instability and high CD8+ T-cell infiltration, confirming their association with immune-reactive tumors. Both CATIM4+MΦ and TLSTIM4+MΦ express FOLR2, a marker of tissue-resident MΦ. However, CATIM4+MΦ had a higher expression of the immunosuppressive molecules TREM2, IL10, and TGFβ as compared with TLSTIM4+MΦ. By analyzing a scRNA sequence data set of tumor-associated myeloid cells, we identified two TIM4+FOLR2+ clusters coherent with CATIM4+MΦ and TLSTIM4+MΦ. We defined specific gene signatures for each subset and found that the CATIM4+ MΦ signature was associated with worse patient survival. In contrast, TLSTIM4+MΦ gene signature positively correlates with a better prognosis. Together, these data illustrate that TIM4 marks two distinct macrophage populations with distinct phenotypes and tissue localization and that may have opposing roles in tumor immunity.

Published
2023

3. Supplementary Table from A Population of TIM4+FOLR2+ Macrophages Localized in Tertiary Lymphoid Structures Correlates to an Active Immune Infiltrate Across Several Cancer Types

Author

William Vermi, Federica Benvenuti, Julie Helft, Yoann Missolo-Koussou, Nicoletta Caronni, Sara Picinoli, Irene Pezzali, Laura Ardighieri, Matilde Monti, Francesco Missale, Marco Bergamini, and Mattia Bugatti

Abstract

Supplementary Table from A Population of TIM4+FOLR2+ Macrophages Localized in Tertiary Lymphoid Structures Correlates to an Active Immune Infiltrate Across Several Cancer Types

Published
2023

4. Supplementary Figure from A Population of TIM4+FOLR2+ Macrophages Localized in Tertiary Lymphoid Structures Correlates to an Active Immune Infiltrate Across Several Cancer Types

Author

William Vermi, Federica Benvenuti, Julie Helft, Yoann Missolo-Koussou, Nicoletta Caronni, Sara Picinoli, Irene Pezzali, Laura Ardighieri, Matilde Monti, Francesco Missale, Marco Bergamini, and Mattia Bugatti

Abstract

Supplementary Figure from A Population of TIM4+FOLR2+ Macrophages Localized in Tertiary Lymphoid Structures Correlates to an Active Immune Infiltrate Across Several Cancer Types

Published
2023

5. Supplementary Data from A Population of TIM4+FOLR2+ Macrophages Localized in Tertiary Lymphoid Structures Correlates to an Active Immune Infiltrate Across Several Cancer Types

Author

William Vermi, Federica Benvenuti, Julie Helft, Yoann Missolo-Koussou, Nicoletta Caronni, Sara Picinoli, Irene Pezzali, Laura Ardighieri, Matilde Monti, Francesco Missale, Marco Bergamini, and Mattia Bugatti

Abstract

Supplementary Data from A Population of TIM4+FOLR2+ Macrophages Localized in Tertiary Lymphoid Structures Correlates to an Active Immune Infiltrate Across Several Cancer Types

Published
2023

6. A population of TIM4+FOLR2+ macrophages localized in tertiary lymphoid structures correlates to an active immune infiltrate across several cancer types

Author

Mattia Bugatti, Marco Bergamini, Francesco Missale, Matilde Monti, Laura Ardighieri, Irene Pezzali, Sara Picinoli, Nicoletta Caronni, Yoann Missolo-Koussou, Julie Helft, Federica Benvenuti, and William Vermi

Subjects
Cancer Research, Tertiary Lymphoid Structures, Macrophages, Immunology, Carcinoma, Humans, Folate Receptor 2, CD8-Positive T-Lymphocytes, Chemokines
Abstract

TIM4 has previously been associated with antitumor immunity, yet the pattern of expression and the function of this receptor across human cancer tissues remain poorly explored. Here we combined extensive immunolabeling of human tissues with in silico analysis of pan-cancer transcriptomic data sets to explore the clinical significance of TIM4 expression. Our results unveil that TIM4 is expressed on a fraction of cavity macrophages (CATIM4+MΦ) of carcinoma patients. Moreover, we uncover a high expression of TIM4 on macrophages of the T-cell zone of the carcinoma-associated tertiary lymphoid structures (TLSTIM4+MΦ). In silico analysis of a pan-cancer data set revealed a positive correlation between TIM4 expression and markers of B cells, effector CD8+ T cells, and a 12-chemokine signature defining tertiary lymphoid structure. In addition, TLSTIM4+MΦ were enriched in cancers displaying microsatellite instability and high CD8+ T-cell infiltration, confirming their association with immune-reactive tumors. Both CATIM4+MΦ and TLSTIM4+MΦ express FOLR2, a marker of tissue-resident MΦ. However, CATIM4+MΦ had a higher expression of the immunosuppressive molecules TREM2, IL10, and TGFβ as compared with TLSTIM4+MΦ. By analyzing a scRNA sequence data set of tumor-associated myeloid cells, we identified two TIM4+FOLR2+ clusters coherent with CATIM4+MΦ and TLSTIM4+MΦ. We defined specific gene signatures for each subset and found that the CATIM4+ MΦ signature was associated with worse patient survival. In contrast, TLSTIM4+MΦ gene signature positively correlates with a better prognosis. Together, these data illustrate that TIM4 marks two distinct macrophage populations with distinct phenotypes and tissue localization and that may have opposing roles in tumor immunity.

Published
2022

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