Abstract

Simple SummaryPancreatic ductal adenocarcinoma (PDAC) causes massive medical problems because of late diagnosis and limited responsiveness to standard chemotherapeutic treatments. This makes PDAC one of the major causes of death by cancer. To address this problem, novel tools for early diagnosis and therapy are needed. The recent development of PDAC organoids, which represent micro-scale mini-tumors, offers promising new options for personalized drug-testing based on primary PDAC patient material. This overview article summarizes and discusses the current state-of-the-art in exploiting the organoid technology to improve clinical management of PDAC.Pancreatic ductal adenocarcinoma (PDAC) represents 90% of pancreatic malignancies. In contrast to many other tumor entities, the prognosis of PDAC has not significantly improved during the past thirty years. Patients are often diagnosed too late, leading to an overall five-year survival rate below 10%. More dramatically, PDAC cases are on the rise and it is expected to become the second leading cause of death by cancer in western countries by 2030. Currently, the use of gemcitabine/nab-paclitaxel or FOLFIRINOX remains the standard chemotherapy treatment but still with limited efficiency. There is an urgent need for the development of early diagnostic and therapeutic tools. To this point, in the past 5 years, organoid technology has emerged as a revolution in the field of PDAC personalized medicine. Here, we are reviewing and discussing the current technical and scientific knowledge on PDAC organoids, their future perspectives, and how they can represent a game change in the fight against PDAC by improving both diagnosis and treatment options.

Highlights

  • Simple Summary: Pancreatic ductal adenocarcinoma (PDAC) causes massive medical problems because of late diagnosis and limited responsiveness to standard chemotherapeutic treatments

  • Pancreatic ductal adenocarcinoma (PDAC) is the most frequent form of pancreatic cancer with an incidence in constant progression that will represent the second cause of cancer related death in western countries by 2030 [1,2,3]

  • The “alternative” pathway takes its origin in ductal cells that, through mutations of oncogenes such as GNAS and KRAS [6,7,8], or tumor suppressors such as TP53 and RNF43 [9], form cystic lesions secreting mucin, with intraductal papillary mucinous neoplasia (IPMN) or mucinous cystic neoplasia (MCN) being the most implicated in progression to PDAC [10,11,12,13]

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Summary

PDAC Development and Classification

Pancreatic ductal adenocarcinoma (PDAC) is the most frequent form of pancreatic cancer with an incidence in constant progression that will represent the second cause of cancer related death in western countries by 2030 [1,2,3]. The step on the road towards personalized medicine was patient derived xenografts (PDX) which, in contrast to 2D, recapitulate more closely the primary tumor and allow prediction of drug responses To this point, PDX were generated with a heterogenous success rate from PDAC primary tumors, fine needle aspiration (FNA), and metastases [35,36,37,38,39,40,41,42]. 3D organoids reproduce largely the morphology, gene and protein expression, cell polarity, and cellular metabolic heterogeneity of the primary tumor, and they appear to be genetically stable over serial passages, which makes them an ideal tool for PDAC modeling and drug testing [44,45,46]

What Is an Organoid?
Establishment of Mouse and Human PDAC Organoids
The “PDACoids”
Towards a Chemically Defined PDAC Organoid Culture
Sources of PDAC Organoids
Findings
CTC-Derived Organoids
Full Text
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