[SCItalk] Galectin-1 and Pancreatic Tumor Microenvironment: Opportunities for Clinical Translations
Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), Spain
Pancreatic ductal adenocarcinoma (PDA) is one of the most lethal tumor types, with extremely low survival rates due to late diagnosis and resistance to standard therapies. Identification of new molecular targets and biomarkers is, therefore, an urgent need to improve this pessimistic scenario. Here, we analyze the potential use of galectin-1 (Gal1), a glycan-binding protein that is highly overexpressed in PDA stroma, as a therapeutic target and biomarker for PDA. Using genetically engineered mouse models (Gal1 knockout mice and mouse models of PDA) and a human cell-based system we found that inhibition of Gal1 leads to impaired tumor formation and metastasis, through modulation of multiple events including proliferation, angiogenesis and immune response, highlighting the high therapeutic value of Gal1 inhibition for PDA treatment. Furthermore, we have shown that Gal1 levels in plasma are increased in PDA patients in comparison to healthy controls and that high level of this protein correlates with lower patient survival, indicating that detection of Gal1 circulating levels can be used as a novel biomarker for detection and prognostics of PDA patients.
I joined the IMIM in 1999, as a group leader at the Cellular and Molecular Biology Unit. From 2008 to 2018, I have been the head of the Molecular Mechanisms of Tumorigenesis group and currently of the “Galectins, Gene Expression Control and Cancer group. Since October 2018 I am also Principal Investigator at IIBB-CSIC, where I am the head of the Molecular Mechanisms of Cancer group. The research carried out in my laboratory has been focused on elucidating the molecular mechanisms underlying the pathogenesis of cancer. My previous scientific background in skin cancer using chemical carcinogenesis mouse models during my PhD (Madrid, 1989-1992) together with further training in angiogenesis during my postdoctoral stay (Milan, Italy, 1993-1999) has provided me with a solid expertise in cancer biology and experimental in vitro and in vivo models. This training together with my previous university pharmacy studies has directed my interests to study cancer with a high translational vision. Accordingly, during the last 19 years, my group has pioneered several research lines identifying new targets for cancer treatment: i) First, we identify the molecular mechanisms responsible for the pathological and pro-tumoral effects of tissue-plasminogen activator (tPA), a serin-protease that is overexpressed in several solid tumors. These data led to the identification for the first time of Galectin-1 as a tPA receptor, generating a new research line in our group aimed to explore the role of this lectin beyond tPA interaction. ii) Thus, using genetically engineered mouse models mimicking cancer progression and Galectin-1 knockout mice we provided in vivo data supporting a key role for Galectin-1 in promoting pancreatic carcinogenesis through activation of tumor-microenvironment crosstalk, favoring key steps of cancer progression, as proliferation, angiogenesis, desmoplasia, immune evasion and metaplasia. iii) Finally, considering that cancer is a genetic disease caused by changes in gene expression during malignant transformation, we are also very interested in deciphering how these genetic changes are regulated. In 2012, we demonstrate that the regulation of RNA translation through the RNA binding protein CPEB4 is a new mechanism for gene expression reprogramming during tumor progression, providing a new layer of complexity in the regulation of gene expression in cancer. These two last discoveries (role of Galectin-1 and CPEB4 in cancer) have paved the way to the current research lines in our group.
These research projects have been developed by the support of continuous competitive research grants as PI (14 national grants and 1 international grant) and 3 contracts with pharmaceutical companies. Our results have also led to 3 patents. I have directed 8 doctoral theses and 2 more are ongoing. My research as group leader has resulted in 27 articles in peer-reviewed journals, 16 of them as senior author, including high impact factor journals as EMBO Journal, Gastroenterology, Nature Medicine, and PNAS; and 10 articles as a collaborator, also in high impact factor journals as Gastroenterolgy, Genome Research, and Nature.
Finally, I am very collaborative and hold several intra- and extramural collaborations. In particular intramural research projects involve collaborations with oncologists and pathologist from Hospital del Mar (shared publications and grants) and with other PIs at IMIM, for pharmacology system projects). We have also extramural collaborations with world-leading investigators in our current topics such as Drs. Gabriel Rabinovich and H.J. Gabius (Galectin-1 field), and Drs. Raúl Méndez and Juana Díez (RNA translation field).
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