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Article ; Online: Metabolic reprogramming in the CLL TME; potential for new therapeutic targets.

Simon-Molas, Helga / Montironi, Chiara / Kabanova, Anna / Eldering, Eric

2024

Abstract: Chronic lymphocytic leukemia (CLL) cells circulate between peripheral (PB) blood and lymph node (LN) compartments, and strictly depend on microenvironmental factors for proliferation, survival and drug resistance. All cancer cells display metabolic ... ...

Abstract	Chronic lymphocytic leukemia (CLL) cells circulate between peripheral (PB) blood and lymph node (LN) compartments, and strictly depend on microenvironmental factors for proliferation, survival and drug resistance. All cancer cells display metabolic reprogramming and CLL is no exception - though the inert status of the PB CLL cells has hampered detailed insight into these processes. We summarize previous work on reactive oxygen species (ROS), oxidative stress, and hypoxia, as well as the important roles of Myc, and PI3K/Akt/mTor pathways. In vitro co-culture systems and gene expression analyses have provided a partial picture of CLL LN metabolism. New broad omics techniques allow to obtain molecular and also single-cell level understanding of CLL plasticity and metabolic reprogramming. We summarize recent developments and describe the new concept of glutamine addiction for CLL, which may hold therapeutic promise.
Language	English
Publishing date	2024-02-15
Publishing country	United States
Document type	Journal Article
ZDB-ID	206923-4
ISSN	1532-8686 ; 0037-1963
ISSN (online)	1532-8686
ISSN	0037-1963
DOI	10.1053/j.seminhematol.2024.02.001
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Article ; Online: Rapid weight loss and jaundice in an adult female.

Núñez-Pizarro, Jorge Luis / Toapanta, David / Montironi, Carla / Zapatero, Juliana

Journal of hepatology

2023 Volume 79, Issue 5, Page(s) e182–e184

MeSH term(s)	Adult ; Humans ; Female ; Infant, Newborn ; Jaundice/diagnosis ; Jaundice/etiology ; Jaundice, Neonatal ; Weight Loss
Language	English
Publishing date	2023-07-16
Publishing country	Netherlands
Document type	Case Reports
ZDB-ID	605953-3
ISSN	1600-0641 ; 0168-8278
ISSN (online)	1600-0641
ISSN	0168-8278
DOI	10.1016/j.jhep.2023.08.028
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Zs.A 2027: Show issues

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Article: Hematopoietic versus Solid Cancers and T Cell Dysfunction: Looking for Similarities and Distinctions.

Montironi, Chiara / Muñoz-Pinedo, Cristina / Eldering, Eric

Cancers

2021 Volume 13, Issue 2

Abstract: Cancer cells escape, suppress and exploit the host immune system to sustain themselves, and the tumor microenvironment (TME) actively dampens T cell function by various mechanisms. Over the last years, new immunotherapeutic approaches, such as adoptive ... ...

Abstract	Cancer cells escape, suppress and exploit the host immune system to sustain themselves, and the tumor microenvironment (TME) actively dampens T cell function by various mechanisms. Over the last years, new immunotherapeutic approaches, such as adoptive chimeric antigen receptor (CAR) T cell therapy and immune checkpoint inhibitors, have been successfully applied for refractory malignancies that could only be treated in a palliative manner previously. Engaging the anti-tumor activity of the immune system, including CAR T cell therapy to target the CD19 B cell antigen, proved to be effective in acute lymphocytic leukemia. In low-grade hematopoietic B cell malignancies, such as chronic lymphocytic leukemia, clinical outcomes have been tempered by cancer-induced T cell dysfunction characterized in part by a state of metabolic lethargy. In multiple myeloma, novel antigens such as BCMA and CD38 are being explored for CAR T cells. In solid cancers, T cell-based immunotherapies have been applied successfully to melanoma and lung cancers, whereas application in e.g., breast cancer lags behind and is modestly effective as yet. The main hurdles for CAR T cell immunotherapy in solid tumors are the lack of suitable antigens, anatomical inaccessibility, and T cell anergy due to immunosuppressive TME. Given the wide range of success and failure of immunotherapies in various cancer types, it is crucial to comprehend the underlying similarities and distinctions in T cell dysfunction. Hence, this review aims at comparing selected, distinct B cell-derived versus solid cancer types and at describing means by which malignant cells and TME might dampen T cell anti-tumor activity, with special focus on immunometabolism. Drawing a meaningful parallel between the efficacy of immunotherapy and the extent of T cell dysfunction will shed light on areas where we can improve immune function to battle cancer.
Language	English
Publishing date	2021-01-14
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers13020284
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Article ; Online: Metabolic signature and response to glutamine deprivation are independent of p53 status in B cell malignancies.

Montironi, Chiara / Chen, Zhenghao / Derks, Ingrid A M / Cretenet, Gaspard / Krap, Esmée A / Eldering, Eric / Simon-Molas, Helga

iScience

2024 Volume 27, Issue 5, Page(s) 109640

Abstract: The tumor suppressor p53 has been described to control various aspects of metabolic reprogramming in solid tumors, but in B cell malignancies that role is as yet unknown. We generated pairs of p53 functional and knockout (KO) clones from distinct B cell ... ...

Abstract	The tumor suppressor p53 has been described to control various aspects of metabolic reprogramming in solid tumors, but in B cell malignancies that role is as yet unknown. We generated pairs of p53 functional and knockout (KO) clones from distinct B cell malignancies (acute lymphoblastic leukemia, chronic lymphocytic leukemia, diffuse large B cell lymphoma, and multiple myeloma). Metabolomics and isotope tracing showed that p53 loss did not drive a common metabolic signature. Instead, cell lines segregated according to cell of origin. Next, we focused on glutamine as a crucial energy source in the B cell tumor microenvironment. In both
Language	English
Publishing date	2024-03-28
Publishing country	United States
Document type	Journal Article
ISSN	2589-0042
ISSN (online)	2589-0042
DOI	10.1016/j.isci.2024.109640
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Article: Targeted transcriptomic analysis of pancreatic adenocarcinoma in EUS-FNA samples by NanoString technology.

Pedrosa, L / Araujo, I K / Cuatrecasas, M / Soy, G / López, S / Maurel, J / Sánchez-Montes, C / Montironi, C / Saurí, T / Sendino, O / Pérez, F M / Ausania, F / Fernández-Esparrach, G / Espósito, F M / Vaquero, E C / Ginès, A

Frontiers in molecular biosciences

2023 Volume 10, Page(s) 1161893

Abstract: Background: ...

Abstract	Background:
Language	English
Publishing date	2023-05-17
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2814330-9
ISSN	2296-889X
ISSN	2296-889X
DOI	10.3389/fmolb.2023.1161893
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Article: New Drugs Effective in the Systemic Treatment of Hepatocellular Carcinoma.

Montironi, Carla / Montal, Robert / Llovet, Josep M

Clinical liver disease

2019 Volume 14, Issue 2, Page(s) 56–61

Language	English
Publishing date	2019-09-02
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	2657644-2
ISSN	2046-2484
ISSN	2046-2484
DOI	10.1002/cld.796
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Article ; Online: Restrospective reappraisal of the prognostic classification of spitzoid melanocytic neoplasms after BRAF and NRAS mutation characterisation: a single institution experience.

Moysset, Irene / Castrejon, Natalia / Garcia-Herrera, Adriana / Castillo, Paola / Marginet, Marta / Teixido, Cristina / Podlipnik, Sebastian / Albero-Gonzalez, Raquel / Montironi, Carla / Navarro, Judit / Rovira, Carlota / Puig, Susana / Carrera, Cristina / Alos, Llucia

Histopathology

2024 Volume 84, Issue 7, Page(s) 1154–1166

Abstract: Aims: The current WHO classification of melanocytic tumours excludes neoplasms showing BRAF or NRAS mutations from the Spitz category. This study aimed to review and reclassify atypical melanocytic tumours with spitzoid morphological features diagnosed ... ...

Abstract	Aims: The current WHO classification of melanocytic tumours excludes neoplasms showing BRAF or NRAS mutations from the Spitz category. This study aimed to review and reclassify atypical melanocytic tumours with spitzoid morphological features diagnosed between 2009 and 2021 in our hospital after expanding the molecular profile, including BRAF and NRAS mutations in all cases. Methods and results: A total of 71 neoplasms showing spitzoid features (Spitz-like) and atypia were included. The risk of progression of tumours was first studied by integrating the morphology, immunohistochemistry (p16, Ki67, HMB45 and PRAME) and fluorescence in-situ hybridisation (FISH) results (melanoma multiprobe and 9p21). In a second step, after expanding the molecular study, including BRAF and NRAS mutational status, the neoplasms were finally classified into four subgroups: atypical Spitz tumour (AST, n = 45); BRAF-mutated naevus/low-grade melanocytoma with spitzoid morphology (BAMS, n = 2); Spitz melanoma (SM, n = 14); and BRAF or NRAS mutated melanoma with spitzoid features (MSF, n = 10). Follow-up of patients revealed uneventful results for AST and BAMS. Only one SM presented lymph node metastasis after 134 months. Conversely, patients with MSF showed an unfavourable outcome: three developed lymph node metastases after a mean time of 22 months, with one patient presenting distant metastasis and dying of the disease 64 months from diagnosis. The progression-free survival showed significant differences between the four groups of spitzoid tumours (P < 0.001) and between both melanoma subtypes (P = 0.012). Conclusions: The classification and prognostication of atypical neoplasms with spitzoid features requires the integration of histomorphology with the molecular investigation of tumours, which should include BRAF and NRAS mutational status.
MeSH term(s)	Humans ; Biomarkers, Tumor/genetics ; GTP Phosphohydrolases/genetics ; Melanoma/genetics ; Melanoma/pathology ; Melanoma/classification ; Melanoma/diagnosis ; Membrane Proteins/genetics ; Mutation ; Nevus, Epithelioid and Spindle Cell/genetics ; Nevus, Epithelioid and Spindle Cell/pathology ; Prognosis ; Proto-Oncogene Proteins B-raf/genetics ; Retrospective Studies ; Skin Neoplasms/genetics ; Skin Neoplasms/pathology ; Skin Neoplasms/classification ; Skin Neoplasms/diagnosis
Chemical Substances	Biomarkers, Tumor ; BRAF protein, human (EC 2.7.11.1) ; GTP Phosphohydrolases (EC 3.6.1.-) ; Membrane Proteins ; NRAS protein, human (EC 3.6.1.-) ; Proto-Oncogene Proteins B-raf (EC 2.7.11.1)
Language	English
Publishing date	2024-02-26
Publishing country	England
Document type	Journal Article
ZDB-ID	131914-0
ISSN	1365-2559 ; 0309-0167
ISSN (online)	1365-2559
ISSN	0309-0167
DOI	10.1111/his.15160
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Zs.A 1328: Show issues

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Article ; Online: T-cell dysfunction by pseudohypoxia and autocrine purinergic signaling in chronic lymphocytic leukemia.

Montironi, Chiara / Jacobs, Chaja F / Cretenet, Gaspard / Peters, Fleur S / Schomakers, Bauke V / van Weeghel, Michel / Kater, Arnon P / Simon-Molas, Helga / Eldering, Eric

Blood advances

2023 Volume 7, Issue 21, Page(s) 6540–6552

Abstract: Acquired T-cell dysfunction is common in chronic B-cell malignancies. Given the strong connection between T-cell metabolism and function, we investigated metabolic alterations as the basis of T-cell dysfunction induced by malignant cells. Using B-cell ... ...

Abstract	Acquired T-cell dysfunction is common in chronic B-cell malignancies. Given the strong connection between T-cell metabolism and function, we investigated metabolic alterations as the basis of T-cell dysfunction induced by malignant cells. Using B-cell malignant cell lines and human peripheral blood mononuclear cells, we first established a model that recapitulates major aspects of cancer-induced T-cell dysfunction. Cell lines derived from chronic lymphocytic leukemia (CLL) (PGA-1, CII, and Mec-1), but not from other B-cell malignancies, altered the T-cell metabolome by generating a pseudohypoxic state. T cells were retained in aerobic glycolysis and were not able to switch to oxidative phosphorylation (OXPHOS). Moreover, T cells produced immunosuppressive adenosine that negatively affected function by dampening the activation, which could be restored by the blocking of adenosine receptors. Subsequently, we uncovered a similar hypoxic-like signature in autologous T cells from primary CLL samples. Pseudohypoxia was reversible upon depletion of CLL cells ex vivo and, importantly, after the in vivo reduction of the leukemic burden with combination therapy (venetoclax and obinutuzumab), restoring T-cell function. In conclusion, we uncovered a pseudohypoxic program connected with T-cell dysfunction in CLL. Modulation of hypoxia and the purinergic pathway might contribute to therapeutic restoration of T-cell function.
MeSH term(s)	Humans ; Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy ; Leukocytes, Mononuclear/metabolism ; T-Lymphocytes/metabolism ; B-Lymphocytes/metabolism ; Oxidative Phosphorylation
Language	English
Publishing date	2023-06-21
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2915908-8
ISSN	2473-9537 ; 2473-9529
ISSN (online)	2473-9537
ISSN	2473-9529
DOI	10.1182/bloodadvances.2023010305
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Article ; Online: Porto-sinusoidal vascular disorder in chronic HBV: A significant coexistence not to be overlooked.

Olivas, Pol / Perez-Campuzano, Valeria / Orts, Lara / Montironi, Carla / Magaz, Marta / Ruiz, Pablo / Shalaby, Sarah / Ojeda, Asunción / Rosich, Pau / Baiges, Anna / Turon, Fanny / Lens, Sabela / García Pagán, Juan Carlos / Hernández-Gea, Virginia

JHEP reports : innovation in hepatology

2023 Volume 6, Issue 3, Page(s) 100996

Abstract: Background & aims: Porto-sinusoidal vascular disorder (PSVD) encompasses a group of liver diseases with vascular abnormalities that can cause portal hypertension in the absence of cirrhosis. The new diagnostic criteria allow for coexistence with other ... ...

Abstract	Background & aims: Porto-sinusoidal vascular disorder (PSVD) encompasses a group of liver diseases with vascular abnormalities that can cause portal hypertension in the absence of cirrhosis. The new diagnostic criteria allow for coexistence with other liver diseases, however its relationship with chronic hepatitis B (CHB) remains unclear. This study aimed to assess HBV prevalence in a PSVD cohort and evaluate its clinical impact. Methods: This retrospective study was conducted on patients with PSVD at Hospital Clínic Barcelona. HBV serology was evaluated, and patients were categorized into HBV chronic infection, past infection, or no HBV exposure. Clinical characteristics and outcomes were compared. Results: We included 155 patients with PSVD. Prevalence of CHB and past HBV infection in patients with PSVD was higher than in the general population (5.8% Conclusions: Recognizing the coexistence of PSVD and CHB is important for timely diagnosis and optimal management, highlighting the potential benefits of specialized care for potentially improved outcomes. Impact and implications: The new diagnostic criteria for porto-sinusoidal vascular disorder (PSVD) allow for coexistence with other liver diseases. The results of the present study highlight, for the first time, a non-negligible prevalence of chronic hepatitis B in the PSVD population that was previously unknown. Coexistence may challenge and delay the PSVD diagnosis and is associated with a more unfavorable clinical course. Our findings will increase awareness of this coexistence and improve PSVD diagnosis and management. Furthermore, the data will encourage new studies to determine the prevalence and clinical behavior of other chronic liver diseases that coexist with PSVD.
Language	English
Publishing date	2023-12-27
Publishing country	Netherlands
Document type	Journal Article
ISSN	2589-5559
ISSN (online)	2589-5559
DOI	10.1016/j.jhepr.2023.100996
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Article ; Online: Combined WNT-activated deep-penetrating/plexiform melanocytoma: insights into clinicopathological and molecular characterization.

Castillo, Paola / Castrejon, Natalia / Marginet, Marta / Massi, Daniela / Alamon, Francesc / Teixido, Cristina / Montironi, Carla / Garcia-Herrera, Adriana / Albero-Gonzalez, Raquel / Matas, Jessica / Puig, Susana / Alos, Llucia

Clinical and experimental dermatology

2023 Volume 49, Issue 4, Page(s) 356–363

Abstract: Background: A combined deep-penetrating tumour redefined as WNT-activated deep-penetrating/plexiform melanocytoma (DPM), may pose challenging clinical and histological diagnoses.: Objectives: To review the clinicopathological characteristics of ... ...

Abstract	Background: A combined deep-penetrating tumour redefined as WNT-activated deep-penetrating/plexiform melanocytoma (DPM), may pose challenging clinical and histological diagnoses. Objectives: To review the clinicopathological characteristics of combined DPMs and characterize the molecular profile of atypical and malignant forms. Methods: The study included 51 patients with combined DPMs diagnosed at the Hospital Clinic of Barcelona and the University of Florence between 2012 and 2020. Clinical data, dermoscopy images (when available) and histological characteristics were reviewed. Immunohistochemistry for β-catenin, LEF1, HMB45, Ki67, p16 and PRAME (preferentially expressed antigen in melanoma) was performed. Atypical forms underwent next-generation sequencing (NGS) panel analysis, including driver genes implicated in DPMs, TERT-promoter (p) mutations and the investigation of the 9p21 locus via fluorescence in situ hybridization. Results: Among the 51 patients (32 females and 19 males, age range 4-74 years), 68% with available clinical data (15/22) were initially suspected of having melanoma. Except for one patient, complete excision resulted in no recurrences or metastases. One patient who had an incompletely excised combined DPM developed a lymph node melanoma metastasis 10 years later. In the 51 patients, 10 samples (20%) showed atypical histological features; 7 (14%) exhibited a significant loss of p16 expression; and 2 (4%) showed a high-proliferative index (Ki67 over 5%). NGS analysis in 11 patients revealed a double mutation BRAFV600E and exon 3 CTNNB1; no TERTp mutations were detected. Conclusions: Clinical suspicion of melanoma is common in combined DPMs, but malignant progression is infrequent in tumours lacking high-grade atypia or proliferation. These findings are congruent with the consideration of these lesions as intermediate-grade tumours or melanocytomas.
MeSH term(s)	Male ; Female ; Humans ; Child, Preschool ; Child ; Adolescent ; Young Adult ; Adult ; Middle Aged ; Aged ; Melanoma/diagnosis ; Melanoma/genetics ; Melanoma/metabolism ; Ki-67 Antigen/metabolism ; In Situ Hybridization, Fluorescence ; Nevus, Epithelioid and Spindle Cell ; Lymphatic Metastasis ; Skin Neoplasms/diagnosis ; Skin Neoplasms/genetics ; Skin Neoplasms/pathology ; Mutation ; Antigens, Neoplasm ; Succinimides
Chemical Substances	3-(3,5-dichlorophenyl)-1-methyl-2,5-pyrrolidinedione (93553-55-0) ; Ki-67 Antigen ; PRAME protein, human ; Antigens, Neoplasm ; Succinimides
Language	English
Publishing date	2023-11-15
Publishing country	England
Document type	Journal Article
ZDB-ID	195504-4
ISSN	1365-2230 ; 0307-6938
ISSN (online)	1365-2230
ISSN	0307-6938
DOI	10.1093/ced/llad405
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