bims-tuchim 2022-01-16 papers

Front Cell Dev Biol. 2021 ;9 761807

Microfluidic Platforms for High-Throughput Pancreatic Ductal Adenocarcinoma Organoid Culture and Drug Screening.

Pancreatic Ductal Adenocarcinoma (PDAC), the most common pancreatic cancer type, is believed to become the second leading cause of cancer-related deaths by 2030 with mortality rates of up to 93%. It is often detected at a late stage due to lacking symptoms, and therefore surgical removal of the tumor is the only treatment option for patients. Only 20% of the tumors are resectable, mainly due to early metastasis. Therefore, for 80% of cases chemotherapeutic treatment is the leading therapy for patients. PDAC is characterized by high-density stroma which induces hypoxic conditions and high interstitial pressure. These factors impact carcinogenesis and progression of PDAC and support the formation of an immunosuppressive microenvironment that renders this tumor type refractory to immunotherapies. Most in vitro PDAC models have limited translational relevance, as these fail to recapitulate relevant aspects of PDAC complexity. Altogether, there is an urgent need for novel and innovative PDAC modeling platforms. Here, we discuss the relevance of microfluidic and organoid technologies as platforms for modeling bio- and physicochemical features of PDAC and as translational models that enable high-throughput phenotypic drug screenings, while also allowing for the development of novel personalized models used to identify treatment responsive patient subsets.

Keywords: PDAC; drug screening; organ-on-a chip; organoids; tumor microenvionment

DOI: https://doi.org/10.3389/fcell.2021.761807

Cancers (Basel). 2021 Dec 31. pii: 194. [Epub ahead of print]14(1):

Macrophage and Neutrophil Interactions in the Pancreatic Tumor Microenvironment Drive the Pathogenesis of Pancreatic Cancer.

Hillary G Pratt, Kayla J Steinberger, Nicole E Mihalik, Sascha Ott, Thomas Whalley, Barbara Szomolay, Brian A Boone, Timothy D Eubank.

Despite modest improvements in survival in recent years, pancreatic adenocarcinoma remains a deadly disease with a 5-year survival rate of only 9%. These poor outcomes are driven by failure of early detection, treatment resistance, and propensity for early metastatic spread. Uncovering innovative therapeutic modalities to target the resistance mechanisms that make pancreatic cancer largely incurable are urgently needed. In this review, we discuss the immune composition of pancreatic tumors, including the counterintuitive fact that there is a significant inflammatory immune infiltrate in pancreatic cancer yet anti-tumor mechanisms are subverted and immune behaviors are suppressed. Here, we emphasize how immune cell interactions generate tumor progression and treatment resistance. We narrow in on tumor macrophage (TAM) spatial arrangement, polarity/function, recruitment, and origin to introduce a concept where interactions with tumor neutrophils (TAN) perpetuate the microenvironment. The sequelae of macrophage and neutrophil activities contributes to tumor remodeling, fibrosis, hypoxia, and progression. We also discuss immune mechanisms driving resistance to standard of care modalities. Finally, we describe a cadre of treatment targets, including those intended to overcome TAM and TAN recruitment and function, to circumvent barriers presented by immune infiltration in pancreatic adenocarcinoma.

Keywords: PDAC; adenocarcinoma; cancer; hypoxia; immunosuppression; macrophage; metastasis; neutrophil; pancreas

DOI: https://doi.org/10.3390/cancers14010194

Cancers (Basel). 2021 Dec 21. pii: 5. [Epub ahead of print]14(1):

Microfluidic-Assisted Preparation of Targeted pH-Responsive Polymeric Micelles Improves Gemcitabine Effectiveness in PDAC: In Vitro Insights.

Rosa Maria Iacobazzi, Ilaria Arduino, Roberta Di Fonte, Angela Assunta Lopedota, Simona Serratì, Giuseppe Racaniello, Viviana Bruno, Valentino Laquintana, Byung-Chul Lee, Nicola Silvestris, Francesco Leonetti, Nunzio Denora, Letizia Porcelli, Amalia Azzariti.

Pancreatic ductal adenocarcinoma (PDAC) represents a great challenge to the successful delivery of the anticancer drugs. The intrinsic characteristics of the PDAC microenvironment and drugs resistance make it suitable for therapeutic approaches with stimulus-responsive drug delivery systems (DDSs), such as pH, within the tumor microenvironment (TME). Moreover, the high expression of uPAR in PDAC can be exploited for a drug receptor-mediated active targeting strategy. Here, a pH-responsive and uPAR-targeted Gemcitabine (Gem) DDS, consisting of polymeric micelles (Gem@TpHResMic), was formulated by microfluidic technique to obtain a preparation characterized by a narrow size distribution, good colloidal stability, and high drug-encapsulation efficiency (EE%). The Gem@TpHResMic was able to perform a controlled Gem release in an acidic environment and to selectively target uPAR-expressing tumor cells. The Gem@TpHResMic displayed relevant cellular internalization and greater antitumor properties than free Gem in 2D and 3D models of pancreatic cancer, by generating massive damage to DNA, in terms of H2AX phosphorylation and apoptosis induction. Further investigation into the physiological model of PDAC, obtained by a co-culture of tumor spheroids and cancer-associated fibroblast (CAF), highlighted that the micellar system enhanced the antitumor potential of Gem, and was demonstrated to overcome the TME-dependent drug resistance. In vivo investigation is warranted to consider this new DDS as a new approach to overcome drug resistance in PDAC.

Keywords: active drug targeting; controlled release; drug delivery; drug resistance; pH-responsiveness; pancreatic ductal adenocarcinoma; tumor microenvironment; uPAR

DOI: https://doi.org/10.3390/cancers14010005