Gender differences in the plasma concentration of the GAS6-TAM system in COVID-19 patients

Resumen del trabajo presentado en el 4th European Congress on Thrombosis and Haemostasis, celebrado en Gante (Bélgica), los días 14 y 15 de octubre de 2021Background: SARS-CoV-2 induces an immune response with potentially harmful effects for the patient due to an uncontrolled release of inflammatory factors, specially at the capillary wall. The vitamin K-dependent plasma protein GAS6 and the TAM (TYRO3, AXL, and MERTK) receptors play a relevant role among restorative mechanisms that counterbalance pro-inflammatory responses at the endothelial interface. Aims: To study the influence of gender on the effects of SARS-CoV-2 infection in the GAS6/TAM system, as reflected by plasma concentration at patient admittance at the emergency ward. Methods: The plasma content of GAS6, AXL, and MERTK was analyzed in a first group of 132 patients, 68 females and 64 males consecutively admitted to the emergency ward during the first peak of COVID-19. A confirmatory group was studied from the second wave of contagions. An analysis of gender differences in relation to the GAS6/TAM concentrations in plasma was performed on this population. Results: In accordance with recently published GAS6 levels, significantly higher in the SARS-CoV-2 positive than in negative patients, increased progressively with the severity of the disease in SARS-CoV-2 positive individual irrespective of the gender of the patient. In contrast, while soluble AXL exhibited higher plasma concentration in deceased patients and no significant differences were observed in MERTK concentration, differential gender analysis suggest differences in soluble TAM receptors. While a COVID-19 related increase in sAXL was observed in men, this was not the case in women. Oppositely, MERTK differences due to COVID-19 infection were only significant in women. Summary/Conclusion: GAS6-TAM system of ligands and receptors is implicated in the immune response to SARS-CoV-2 in patients from both genders. Plasma GAS6 levels paralleled COVID-19 severity being an early marker of disease prognosis in both sexes. In contrast, soluble TAM receptors presented a gender-specific behavior. Sex-related differences in sAXL and sMERTK expression in COVID-19 patients could affect therapy efficacy deserving further investigation

Galectins in the Tumor Microenvironment: Focus on Galectin-1

In the last decades, the focus of cancer research has moved from epithelial cells to the tumor milieu, in an effort to better understand tumor development and progression, and with the important end goal of translating this knowledge into effective therapies. The galectin family of glycan-binding proteins displays important functions in cancer development and progression. Numerous groups have made outstanding contributions to deepen our knowledge about the role of galectins in the tumor-stroma crosstalk, defining them as key players in modulating interactions between tumor cells and the extracellular matrix, fibroblasts, endothelium, and the immune system. While several members of the family have been of particular interest until now, others are still considered as future exploding stars. This chapter provides an overview for galectin-1, the first identified and still one of the most well-studied galectins, and highlights the very important implications in its regulation of the tumor microenvironment in many different tumor types. Besides, a glimpse of the role of other galectins in the tumor milieu is also provided. Gaining a deeper understanding about the numerous roles of galectin-1 will not only help us to better understand other galectins but also is likely to result in the development of more effective cancer therapies.This work was supported by grants from the Spanish Ministry of Economy and Competitiveness/ISCIII-FEDER (PI17/00199), the Carmen Delgado/ Miguel Pérez-Mateo AESPANC-ACANPAN 2016 grant, and the Generalitat de Catalunya (2017-SGR-225) to P.N. We are also grateful to A. Flotats for help in graphic design and V. Raker for English proofreading and editing.Peer reviewe

Immune Evasion in Pancreatic Cancer: From Mechanisms to Therapy

Pancreatic ductal adenocarcinoma (PDA), the most frequent type of pancreatic cancer, remains one of the most challenging problems for the biomedical and clinical fields, with abysmal survival rates and poor therapy efficiency. Desmoplasia, which is abundant in PDA, can be blamed for much of the mechanisms behind poor drug performance, as it is the main source of the cytokines and chemokines that orchestrate rapid and silent tumor progression to allow tumor cells to be isolated into an extensive fibrotic reaction, which results in inefficient drug delivery. However, since immunotherapy was proclaimed as the breakthrough of the year in 2013, the focus on the stroma of pancreatic cancer has interestingly moved from activated fibroblasts to the immune compartment, trying to understand the immunosuppressive factors that play a part in the strong immune evasion that characterizes PDA. The PDA microenvironment is highly immunosuppressive and is basically composed of T regulatory cells (Tregs), tumor-associated macrophages (TAMs), and myeloid-derived suppressive cells (MDSCs), which block CD8⁺ T-cell duties in tumor recognition and clearance. Interestingly, preclinical data have highlighted the importance of this immune evasion as the source of resistance to single checkpoint immunotherapies and cancer vaccines and point at pathways that inhibit the immune attack as a key to solve the therapy puzzle. Here, we will discuss the molecular mechanisms involved in PDA immune escape as well as the state of the art of the PDA immunotherapy

Galectins in prostate and bladder cancer: tumorigenic roles and clinical opportunities

Advanced prostate and bladder cancer are two outstanding unmet medical needs for urological oncologists. The high prevalence of these tumours, lack of effective biomarkers and limited effective treatment options highlight the importance of basic research in these diseases. Galectins are a family of β-galactoside-binding proteins that are frequently altered (upregulated or downregulated) in a wide range of tumours and have roles in different stages of tumour development and progression, including immune evasion. In particular, altered expression levels of different members of the galectin family have been reported in prostate and bladder cancers, which, together with the aberrant glycosylation patterns found in tumour cells and the constituent cell types of the tumour microenvironment, can result in malignant transformation and tumour progression. Understanding the roles of galectin family proteins in the development and progression of prostate and bladder cancer could yield key insights to inform the clinical management of these diseases.This work was supported by grants from the Spanish Ministry of Economy and Competitiveness/ISCIII-FEDER (PI14/00125 and PI17/00199), an AECC-Cataluña 2015 grant and the Generalitat de Catalunya (2014/SGR/143 and 2017/SGR/225) grant to P.N

Knockdown of α2,3-Sialyltransferases Impairs Pancreatic Cancer Cell Migration, Invasion and E-selectin-Dependent Adhesion

Aberrant sialylation is frequently found in pancreatic ductal adenocarcinoma (PDA). α2,3-Sialyltransferases (α2,3-STs) ST3GAL3 and ST3GAL4 are overexpressed in PDA tissues and are responsible for increased biosynthesis of sialyl-Lewis (sLe) antigens, which play an important role in metastasis. This study addresses the effect of α2,3-STs knockdown on the migratory and invasive phenotype of PDA cells, and on E-selectin-dependent adhesion. Characterization of the cell sialome, the α2,3-STs and fucosyltransferases involved in the biosynthesis of sLe antigens, using a panel of human PDA cells showed differences in the levels of sialylated determinants and α2,3-STs expression, reflecting their phenotypic heterogeneity. Knockdown of ST3GAL3 and ST3GAL4 in BxPC-3 and Capan-1 cells, which expressed moderate to high levels of sLe antigens and α2,3-STs, led to a significant reduction in sLex and in most cases in sLea, with slight increases in the α2,6-sialic acid content. Moreover, ST3GAL3 and ST3GAL4 downregulation resulted in a significant decrease in cell migration and invasion. Binding and rolling to E-selectin, which represent key steps in metastasis, were also markedly impaired in the α2,3-STs knockdown cells. Our results indicate that inhibition of ST3GAL3 and ST3GAL4 may be a novel strategy to block PDA metastasis, which is one of the reasons for its dismal prognosis.This work was funded by the Spanish Ministry of Science and Innovation (grant BIO 2015-66356-R), by the University of Girona grant (MPCUdG2016/028) to R.P. and by the AGAUR-Generalitat de Catalunya grant (2014SGR0229) to R.d.L., and by grants from the Spanish Ministry of Economy and Competitiveness/ISCIII-FEDER (PI17/00199), and the Generalitat de Catalunya (2017-SGR-225) to P.N.Peer reviewe

Increased plasma levels of galectin-1 in pancreatic cancer : potential use as biomarker

Altres ajuts: This work was supported by grants from the Spanish Ministerio de Economía y Competitividad/ISCIII-FEDER, the Carmen Delgado/Miguel Pérez-Mateo AESPANC-ACANPAN 2016 grant and the "Generalitat de Catalunya" to P.N., , EU TRANSCAN AC14/00033 and AECC grants to A.C., and grants from Instituto de Salud Carlos III/FEDER and the "Xarxa de Bancs de tumors" sponsored by Pla Director d'Oncologia de Catalunya (XBTC). CAO received funding from the International PhD studies Fellowship "Créditos Beca Francisco José de Caldas" n° 529-2011 Colciencias, Colombia.Pancreatic ductal adenocarcinoma (PDA) is the most frequent type of pancreatic cancer and one of the deadliest diseases overall. New biomarkers are urgently needed to allow early diagnosis, one of the only factors that currently improves prognosis. Here we analyzed whether the detection of circulating galectin-1 (Gal-1), a soluble carbohydrate-binding protein overexpressed in PDA tissue samples, can be used as a biomarker for PDA. Gal-1 levels were determined by ELISA in plasma from healthy controls and patients diagnosed with PDA, using three independent cohorts. Patients with chronic pancreatitis (CP) were also included in the study to analyze the potential of Gal-1 to discriminate between cancer and inflammatory process. Plasma Gal-1 levels were significantly increased in patients with PDA as compared to controls in all three cohorts. Gal-1 sensitivity and specificity values were similar to that of the CA19-9 biomarker (the only FDA-approved blood test biomarker for PDA), and the combination of Gal-1 and CA19-9 significantly improved their individual discriminatory powers. Moreover, high levels of Gal-1 were associated with lower survival in patients with non-resected tumors. Collectively, our data indicate a strong potential of using circulating Gal-1 levels as a biomarker for detection and prognostics of patients with PDA

Galectin-1 drives pancreatic carcinogenesis through stroma remodeling and Hedgehog signaling activation.

International audience: Despite some advances, pancreatic ductal adenocarcinoma (PDAC) remains generally refractory to current treatments. Desmoplastic stroma, a consistent hallmark of PDAC, has emerged as a major source of therapeutuic resistance and thus potentially promising targets for improved treatment. The glycan-binding protein galectin-1 (Gal1) is highly expressed in PDAC stroma but its roles there have not been studied. Here we report functions and molecular pathways of Gal1 that mediate its oncogenic properties in this setting. Genetic ablation of Gal1 in a mouse model of PDAC (EIa-myc mice) dampened tumor progression by inhibiting proliferation, angiogenesis, desmoplasic reaction and by stimulating a tumor-associated immune response, yielding a 20% increase in relative lifesplan. Cellular analyses in vitro and in vivo suggested these effects were mediated through the tumor microenvironment. Importantly, acinar-to-ductal metaplasia, a crucial step for initiation of PDAC, was found to be regulated by Gal1. Mechanistic investigations revealed that Gal1 promoted Hedgehog pathway signaling, in PDAC cells and stromal fibroblasts as well as in Ela-myc tumors. Taken together, our findings establish a function for Gal1 in tumor-stroma crosstalk in PDAC and provide a preclinical rationale for Gal1 targeting as a microenvironment-based therapeutic strategy

Targeting galectin-1 inhibits pancreatic cancer progression by modulating tumor–stroma crosstalk

Pancreatic ductal adenocarcinoma (PDA) remains one of the most lethal tumor types, with extremely low survival rates due to late diagnosis and resistance to standard therapies. A more comprehensive understanding of the complexity of PDA pathobiology, and especially of the role of the tumor microenvironment in disease progression, should pave the way for therapies to improve patient response rates. In this study, we identify galectin-1 (Gal1), a glycan-binding protein that is highly overexpressed in PDA stroma, as a major driver of pancreatic cancer progression. Genetic deletion of Gal1 in a Kras-driven mouse model of PDA (Ela-KrasG12Vp53−/−) results in a significant increase in survival through mechanisms involving decreased stroma activation, attenuated vascularization, and enhanced T cell infiltration leading to diminished metastasis rates. In a human setting, human pancreatic stellate cells (HPSCs) promote cancer proliferation, migration, and invasion via Gal1-driven pathways. Moreover, in vivo orthotopic coinjection of pancreatic tumor cells with Gal1-depleted HPSCs leads to impaired tumor formation and metastasis in mice. Gene-expression analyses of pancreatic tumor cells exposed to Gal1 reveal modulation of multiple regulatory pathways involved in tumor progression. Thus, Gal1 hierarchically regulates different events implicated in PDA biology including tumor cell proliferation, invasion, angiogenesis, inflammation, and metastasis, highlighting the broad therapeutic potential of Gal1-specific inhibitors, either alone or in combination with other therapeutic modalities.This work was supported by Spanish Ministry of Economy and Competitiveness/ISCIII-FEDER Grants PI14/00125 and PI17/00199, the Carmen Delgado/Miguel Pérez-Mateo Asociación Española de Pancreatología/ Asociación Cáncer de Páncreas 2016 Grant, and Generalitat de Catalunya Grant 2014/SGR/143 (to P.N.). M.E.F.-Z. was supported by Mayo Clinic Pancreatic Specialized Program of Research Excellence Grant P50 CA102701 and Mayo Clinic Center for Cell Signaling in Gastroenterology Grant P30 DK84567. C.A.O. was supported by the International PhD Studies Fellowship Créditos Beca Francisco José de Caldas from the Colombian Administrative Department of Science, Technology and Innovation (Colciencias). M.D. was supported by a fellowship from La Caixa International Fellowship Program. G.A.R. was supported by Argentinean Agency for Promotion of Science and Technology Grant PICT 2014-3687 and by grants from the University of Buenos Aires, the Sales Foundation, and the Bunge and Born Foundation. T.D.-M. is a postdoctoral fellow supported by the Argentine National Scientific and Technical Research Council.Peer reviewe