Abstract
Pancreatic ductal adenocarcinoma (PDAC) is associated with high mortality and will become the second most common cause of cancer-associated mortality by 2030. The poor prognosis arises from a lack of sensitive biomarkers, limited therapeutic options, and the astonishingly high recurrence rate after surgery of 60–80%. The factors driving this recurrence, however, remain enigmatic. Therefore, we generated patient-derived organoids (PDOs) from early- and late-recurrent PDAC patients. Cellular identity of PDOs was confirmed by qPCR, ddPCR, and IHC analyses. This is the first study investigating the metabolism in PDOs of different, clinically significant PDAC entities by untargeted GC/MS profiling. Partial least square discriminant analysis unveiled global alterations between the two sample groups. We identified nine metabolites to be increased in early recurrent PDOs in comparison to late recurrent PDOs. More than four-times increased were fumarate, malate, glutamate, aspartate, and glutamine. Hence, α-keto acids were elevated in PDO-conditioned medium derived from early recurrent patients. We therefore speculate that an increased anaplerotic metabolism fuels the Krebs-cycle and a corresponding higher accessibility to energy fastens the recurrence in PDAC patients. Therein, a therapeutic intervention could delay PDAC recurrence and prolong survival of affected patients or could serve as biomarker to predict recurrence in the future.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is the most common histological subtype of pancreatic cancer and a highly aggressive and fast-growing type of cancer [1,2,3]
We found that patient-derived organoids (PDOs) derived from early recurrent PDAC patients had higher levels of tricarboxylic acid intermediates and some anaplerotic amino acids, suggesting a higher capacity to generate energy
Primary antibodies were diluted in 1% BSA/TBS and slides were incubated with the respective antibodies overnight at 4 ◦ C
Summary
Pancreatic ductal adenocarcinoma (PDAC) is the most common histological subtype of pancreatic cancer and a highly aggressive and fast-growing type of cancer [1,2,3]. The molecular pathology of PDAC is extremely challenging with a 92–95% prevalence in non-druggable activating KRAS mutation next to TP53 and/or CDKN2A alterations driving cancer survival, growth, resistance to therapeutic options and metastasis [18] These factors further contribute to a rapid progression of the disease [19] and support anabolic metabolic pathways [15]. The organoid culture system allows the expansion of primary tissue in an in vitro system which is much closer to the actual patient than established cell lines are. These systems allow the growth of 3D structures from healthy and disease tissue making the direct comparison between both states more convenient [48]. Early recurrence might be the consequence of higher energy levels in these malignancies, suggesting a possible target to delay recurrence in future PDAC therapy or potential biomarkers to predict recurrence
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