Abstract
Simple SummaryPancreatic ductal adenocarcinoma (PDAC) is the most prevalent and aggressive type of pancreatic cancer with a low 5-year survival rate of only 8%. The cellular arrangement plays a crucial role in PDAC, which is characterized by a highly fibrotic environment around the tumor cells, preventing treatments from reaching their target. For the development of novel drug candidates, it is crucial to mimic this cellular arrangement in a laboratory environment. We successfully developed a reproducible three-dimensional cell culture model that demonstrates the PDAC characteristic arrangement and showed a PDAC relevant gene profile when comparing with the genetic profile of PDAC patients. We finally demonstrated the use of the model for the evaluation of novel anti-fibrotic therapy against PDAC by studying drug-induced reduction of fibrosis in PDAC enabling nanoparticles to penetrate and reach the tumor cells. This model is useful for the evaluation of novel treatments against PDAC in a biologically relevant manner.Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive tumor type with low patient survival due to the low efficacy of current treatment options. Cancer-associated fibroblasts (CAFs) in the tumor microenvironment (TME) create a dense fibrotic environment around the tumor cells, preventing therapies from reaching their target. Novel 3D in vitro models are needed that mimic this fibrotic barrier for the development of therapies in a biologically relevant environment. Here, novel PDAC microtissues (µtissues) consisting of pancreatic cancer cell core surrounded by a CAF-laden collagen gel are presented, that is based on the cells own contractility to form a hard-to-penetrate barrier. The contraction of CAFs is demonstrated facilitating the embedding of tumor cells in the center of the µtissue as observed in patients. The µtissues displayed a PDAC-relevant gene expression by comparing their gene profile with transcriptomic patient data. Furthermore, the CAF-dependent proliferation of cancer cells is presented, as well as the suitability of the µtissues to serve as a platform for the screening of CAF-modulating therapies in combination with other (nano)therapies. It is envisioned that these PDAC µtissues can serve as a high-throughput platform for studying cellular interactions in PDAC and for evaluating different treatment strategies in the future.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) accounts for up to 80% of all pancreatic cancers and is characterized by high aggressiveness, late diagnosis and challenging surgical resection due to its complicated localization, as well as a high resistance to treatments [1,2,3].In particular, the low efficacy of current treatments such as chemotherapy contribute to the low five-year patient survival of only 8%, which, even with intensive treatment, might only be prolonged by a couple of months
With the aim to establish an engineered microtissue model that replicates the dense and fibrotic microenvironment found in PDAC, we first investigated the cellular arrangement of tumor cells and cancer-associated fibroblasts (CAFs) based on the immunostaining of tumor sections obtained from PDAC patients (Figure 1A)
We observed that the pancreatic ducts, here identified by a high expression of CK19, in PDAC are surrounded by a high amount of αSMA expressing cells, which in PDAC can be identified as CAFs [10,11]
Summary
Pancreatic ductal adenocarcinoma (PDAC) accounts for up to 80% of all pancreatic cancers and is characterized by high aggressiveness, late diagnosis and challenging surgical resection due to its complicated localization, as well as a high resistance to treatments [1,2,3].In particular, the low efficacy of current treatments such as chemotherapy contribute to the low five-year patient survival of only 8%, which, even with intensive treatment, might only be prolonged by a couple of months. Pancreatic ductal adenocarcinoma (PDAC) accounts for up to 80% of all pancreatic cancers and is characterized by high aggressiveness, late diagnosis and challenging surgical resection due to its complicated localization, as well as a high resistance to treatments [1,2,3]. The increasing number of PDAC patients demonstrates the urgent need for novel therapeutics; only a fraction of potential therapeutics successfully reaches the clinics. One of the major reasons for this low success rate is the tumor microenvironment (TME) in PDAC, in which the tumor stroma forms a dense and hard to overcome barrier for novel therapeutics [1,5,6,7,8,9]. In PDAC this barrier is characterized by an abundance of cancer-associated fibroblasts (CAFs), largely originating from pancreatic stellate cells (PSCs), which produce large amounts of extracellular matrix (ECM)
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