Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a hostile solid malignancy coupled with an extremely high mortality rate. Metastatic disease is already found in most patients at the time of diagnosis, resulting in a 5-year survival rate below 5%. Improved comprehension of the mechanisms leading to metastasis is pivotal for the development of new targeted therapies. A key field to be improved are modeling strategies applied in assessing cancer progression, since traditional platforms fail in recapitulating the complexity of PDAC. Consequently, there is a compelling demand for new preclinical models that mirror tumor progression incorporating the pressure of the immune system, tumor microenvironment, as well as molecular aspects of PDAC. We suggest the incorporation of 3D organoids derived from genetically engineered mouse models or patients as promising new tools capable to transform PDAC pre-clinical modeling and access new frontiers in personalized medicine.

Highlights

  • Pancreatic ductal adenocarcinoma (PDAC) has the worst 5-year relative survival rate in comparison to all other solid tumors and has been prognosed to become the second leading cause of cancerrelated mortality in the United States by 2030 after lung cancer (Chu et al, 2017; McGuigan et al, 2018)

  • This study showed that across the same tumors, epithelial and stromal subtypes were partially linked [Extracellular Matrix (ECM) rich stroma was associated with Basal-like epithelium and Immune-rich stroma was found more often in association with Classical epithelia], showing potential dependence in the evolution of the tissue compartments in PDAC (Maurer et al, 2019)

  • Pancreatic ductal adenocarcinoma is characterized by dense desmoplasia, which can compose up to 80% of the whole tumor volume and low tumor cellularity, while metastases in the liver have less stroma and more tumor cellularity than primary tumors resulting in less overall survival (Rucki, 2014)

Read more

Summary

INTRODUCTION

Pancreatic ductal adenocarcinoma (PDAC) has the worst 5-year relative survival rate in comparison to all other solid tumors and has been prognosed to become the second leading cause of cancerrelated mortality in the United States by 2030 after lung cancer (Chu et al, 2017; McGuigan et al, 2018). Extracellular vesicles and soluble factors are secreted by the primary tumor or premalignant lesions, even before the initiation of PDAC dissemination They help to form a supportive niche in the liver by providing vascular docking sites for CTCs enhancing vascular permeability, remodeling the ECM and gathering immunosuppressive inflammatory cells (Houg and Bijlsma, 2018). Next-generation genome sequencing of untreated pancreatic primary tumors and the corresponding patient metastasis showed that cells triggering distant metastasis are genetically indistinguishable with the different metastatic locus bearing the same driver gene mutations (Makohon-Moore et al, 2017) This implies that post-transcriptional or transcriptional modifications are pivotal to support the intricated series of biological bottlenecks that must be surpassed for PDAC to metastasize (Fidler, 2003; Lambert et al, 2017). There are several undergoing clinical trials of targeted agents designed with patients suffering from locally advanced disease or metastasis (Table 1) hoping to improve patients’ overall survival

Conclusion
Findings
DISCUSSION
Full Text
Published version (Free)

Talk to us

Join us for a 30 min session where you can share your feedback and ask us any queries you have

Schedule a call