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Article summary:
1. Pancreatic ductal adenocarcinoma (PDAC) is a treatment-refractory disease, and current molecular subtyping does not inform clinical management or therapeutic development.
2. Single-cell RNA-seq has been challenging to apply in PDAC due to high intrinsic nuclease activity and dense desmoplastic stroma.
3. This study optimized snRNA-seq for banked frozen PDAC specimens, identified treatment-associated changes in cellular composition and expression programs, and discovered spatially defined intercellular receptor–ligand interactions specifically enhanced in post-treatment residual disease.
Article analysis:
This article provides an overview of the use of single-nucleus RNA sequencing (snRNA-seq) to profile pancreatic ductal adenocarcinoma (PDAC). The authors present their findings on the impact of neoadjuvant chemotherapy and/or radiotherapy on residual cancer cells and stroma, as well as the potential for targeting intercellular receptor–ligand interactions specifically enhanced in post-treatment residual disease.
The article is generally reliable and trustworthy, providing evidence for its claims through data from 224,988 high quality snRNA-seq profiles from 43 patients who underwent surgical resection with or without neoadjuvant treatment. The authors also provide detailed information on the experimental workflow used to collect these profiles, as well as a thorough discussion of their results.
However, there are some potential biases that should be noted. First, the study only included 48 patients out of which 43 were profiled by snRNA-seq; it is unclear why the other five were excluded from this analysis. Second, all treated patients received multicycle chemotherapy followed by multifraction radiotherapy with concurrent fluorouracil/capecitabine (CRT), except for five additional patients enrolled on a clinical trial investigating neoadjuvant CRT with the addition of losartan (CRTL). Thus, it is possible that the results may not be generalizable to other forms of neoadjuvant treatments such as FOLFIRINOX or stereotactic body radiotherapy with nivolumab. Finally, although the authors discuss potential targets for improving neoadjuvant and adjuvant therapy in pancreatic cancer based on their findings, they do not provide any evidence that these targets have been tested or validated in clinical trials.