Tumor Microenvironment Modulates Invadopodia Activity of Non-Selected and Acid-Selected Pancreatic Cancer Cells and Its Sensitivity to Gemcitabine and C18-Gemcitabine

• Published in: Cells (Basel, Switzerland) Switzerland), 2024-05, Vol.13 (9), p.730
• Main Authors: Carvalho, Tiago M A, Audero, Madelaine Magalì, Greco, Maria Raffaella, Ardone, Marilena, Maggi, Teresa, Mallamaci, Rosanna, Rolando, Barbara, Arpicco, Silvia, Ruffinatti, Federico Alessandro, Pla, Alessandra Fiorio, Prevarskaya, Natalia, Koltai, Tomas, Reshkin, Stephan J, Cardone, Rosa Angela
• Format: Article
• Language: English
• Subjects: Acidosis; Adenocarcinoma; Carcinoma, Pancreatic Ductal - drug therapy; Carcinoma, Pancreatic Ductal - metabolism; Carcinoma, Pancreatic Ductal - pathology; Cell culture; Cell death; cell invasion; Cell Line, Tumor; Chemoresistance; Collagen; Cytotoxicity; Deferoxamine; Deoxycytidine - analogs & derivatives; Deoxycytidine - pharmacology; Deoxycytidine - therapeutic use; Drug Resistance, Neoplasm - drug effects; extracellular acidosis; Extracellular matrix; Gemcitabine; Health aspects; Humans; Hypoxia; invadopodia; Medical prognosis; Metastases; Metastasis; Mortality; Pancreatic cancer; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - pathology; Podosomes - drug effects; Podosomes - metabolism; Prodrugs; Prodrugs - pharmacology; Proteins; Proteolysis; Tumor microenvironment; Tumor Microenvironment - drug effects; Tumors
• ISSN: 2073-4409; 2073-4409
• DOI: 10.3390/cells13090730

Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease with high mortality due to early metastatic dissemination and high chemoresistance. All these factors are favored by its extracellular matrix (ECM)-rich microenvironment, which is also highly hypoxic and acidic. Gemcitabine (GEM) is still the first-line therapy in PDAC. However, it is quickly deaminated to its inactive metabolite. Several GEM prodrugs have emerged to improve its cytotoxicity. Here, we analyzed how the acidic/hypoxic tumor microenvironment (TME) affects the response of PDAC cell death and invadopodia-mediated ECM proteolysis to both GEM and its C18 prodrug. For this, two PDAC cell lines, PANC-1 and Mia PaCa-2 were adapted to pH 6.6 or not for 1 month, grown as 3D organotypic cultures and exposed to either GEM or C18 in the presence and absence of acidosis and the hypoxia inducer, deferoxamine. We found that C18 has higher cytotoxic and anti-invadopodia activity than GEM in all culture conditions and especially in acid and hypoxic environments. We propose C18 as a more effective approach to conventional GEM in developing new therapeutic strategies overcoming PDAC chemoresistance.