Metabolic Profiling of Early and Late Recurrent Pancreatic Ductal Adenocarcinoma Using Patient-Derived Organoid Cultures

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.

Plasma biomarkers for prediction of early tumor recurrence after resection of pancreatic ductal adenocarcinoma

“…Establishment of organoid cultures 14 , 15 and determination of KRAS mutational status 16 was achieved as previously described. For passaging, Matrigel domes with organoids were disrupted from a 24-well plate and collected in 10 mL cold splitting medium.…”

Targeting Glutaminolysis: New Perspectives to Understand Cancer Development and Novel Strategies for Potential Target Therapies

“…In addition, suppressing glutamine uptake by inhibiting glutamine transporter ASCT2 significantly inhibited prostate cancer growth and metastasis (96). Moreover, in patient-derived organoids model, Braun et al found that glutamine was increased more than four times from early-recurrent PDAC patients with the development of tumor recurrence within the first six months after radical surgery, than those from late-recurrent patients, suggesting that glutamine metabolism may be diverse according to different tumor malignancies (97). To date, the exact mechanisms linking glutamine metabolism to tumor metastasis are still unclear, but studies have demonstrated that glutamine may participate in the metastatic process through the interaction with EMT, tumor immunology and tumor microenvironment.…”

Construction and validation of a metabolic gene-associated prognostic model for cervical carcinoma and the role on tumor microenvironment and immunity

“…Cervical cancer is the most common gynecological malignancy, which can be primary tumors that derived either from the genitalia or the products of conception, or secondary tumors impacted by other cancerous organs with metastasis [ 12 ]. Metabolism plays a crucial role in the process of tumor initiation, development, and recurrent [ 13 , 14 ]. Metabolic reprogramming was utilized by cancer cells to achieve limited nutrient resources for proliferation, growth, survival, and long-term maintenance when competing with normal cells [ 15 ].…”