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

Abstract

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 -driven mouse model of PDA ( ) 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.

Lack of galectin‐1 exacerbates chronic hepatitis, liver fibrosis, and carcinogenesis in murine hepatocellular carcinoma model

“…Gal1, a prototype member of the galectin family widely expressed at sites of inflammation and tumor growth, can influence tumor progression through multiple mechanisms, including promotion of tumor inflammation, immunosuppression, angiogenesis, and metastasis (11,26). The marked up-regulation of Gal1 in the liver, its protumorigenic effects, and its broad anti-inflammatory activity in a wide variety of pathologic settings prompted us to investigate the role of this glycan-binding protein in CLIdriven HCC development.…”

“…The marked up-regulation of Gal1 in the liver, its protumorigenic effects, and its broad anti-inflammatory activity in a wide variety of pathologic settings prompted us to investigate the role of this glycan-binding protein in CLIdriven HCC development. Targeted inhibition of Lgals1 expression in a variety of tumors, including melanoma cells, Hodgkin lymphoma, lung adenocarcinoma, pancreatic adenocarcinoma, breast adenocarcinoma and glioblastoma, resulted in unleashed antitumor immunity, leading to inhibition of tumor growth and metastasis in syngeneic mice (26)(27)(28)(29)(30). From an immunologic standpoint, this lectin impairs CD8, T h 1, and T h 17; deactivates antigen-presenting cells; inhibits NK cells; and promotes expansion of regulatory T cells (7,29,(31)(32)(33).…”

“…Recently, Rutkowski and colleagues (34) found that this lectin links tumor-promoting inflammation, immunosuppression, and distant tumor growth. Although Gal1 is typically up-regulated in cancer cells, in some tumor types, immune and/or stromal cells appear to be the main Gal1 source (26,34,35). Moreover, Gal1 promotes tumor angiogenesis (13)(14)(15) and augments Ras activation (12).…”

An Integrated Meta-Analysis of Secretome and Proteome Identify Potential Biomarkers of Pancreatic Ductal Adenocarcinoma

“…Pancreatic cancer chemotherapeutic resistance is one of the characteristics that make it so aggressive. Among our protein pool, we found Galectin-1 (LGALS1), a glycan-binding protein that is highly expressed in PDAC stroma, and a significant contributor to pancreatic cancer progression [148]. Increased LGALS1 expression in cancer cells such as lung, liver, ovarian, glioblastoma, and lymphoma has been associated with drug resistance (temozolomide, sorafenib, rituximab, and cisplatin) [149][150][151][152][153][154][155][156].…”

Human Macrophage Galactose‐Type Lectin (MGL) Recognizes the Outer Core of Escherichia coli Lipooligosaccharide

“…Given their ability to selectively recognise carbohydrate structures, human lectins have emerged as potential LPS receptors specifically for their carbohydrate moiety . Lectins are ubiquitous oligomeric proteins that have multiple roles in cell–cell communication, cellular trafficking and regulation of immune cell functions; therefore, representing validated therapeutic targets . Within the many different families of lectins described in humans, to date, the C‐type lectin (CTL) class is the biggest and most diverse, including both transmembrane and soluble receptors.…”