Abstract
Pancreatic ductal adenocarcinoma (PDAC), the most common form of pancreatic cancer, is an extremely lethal disease due to late diagnosis, aggressiveness and lack of effective therapies. Considering its intrinsic heterogeneity, patient stratification models based on transcriptomic and genomic signatures, with partially overlapping subgroups, have been established. Besides molecular alterations, PDAC tumours show a strong desmoplastic response, resulting in profound metabolic reprogramming involving increased glucose and amino acid consumption, as well as lipid scavenging and biosynthesis. Interestingly, recent works have also revealed the existence of metabolic subtypes with differential prognosis within PDAC, which correlated to defined molecular subclasses in patients: lipogenic subtype correlated with a classical/progenitor signature, while glycolytic tumours associated with the highly aggressive basal/squamous profile. Bioinformatic analyses have demonstrated that the representative genes of each metabolic subtype are up-regulated in PDAC samples and predict patient survival. This suggests a relationship between the genetic signature, metabolic profile, and aggressiveness of the tumour. Considering all this, defining metabolic subtypes represents a clear opportunity for patient stratification considering tumour functional behaviour independently of their mutational background.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is considered one of the most aggressive solid malignancies
This study revealed that aberrant K-RAS is implicated in glucose metabolism intermediates channelling into different anabolic pathways, such as the hexosamine biosynthesis pathway (HBP) and pentose phosphate pathway (PPP), proving that glucose metabolism is necessary to fuel anabolic branches of PDAC metabolism to provide the cancer cells with building blocks for its increased proliferation demands [58]
Karasinska et al compared their metabolic classification with previous molecular signatures (Table 4): the quiescent group predominantly belonged to Moffit’s classical subgroup, and it showed the highest frequency of aberrantly differentiated endocrine exocrine” (ADEX) and exocrine-like cases, suggesting that the quiescent group might be involved in the secretion of digestive enzymes; the glycolytic subtype was associated with the basal, squamous and quasi-mesenchymal subgroups, all related with the worst outcome; the cholesterogenic group had the lowest proportion of poor prognosis signatures, but the highest in Bailey’s pancreatic progenitor subtype
Summary
Pancreatic ductal adenocarcinoma (PDAC) is considered one of the most aggressive solid malignancies. The only available curative option for PDAC patients is surgical resection followed by adjuvant chemotherapy [4]. This occurs in a minority of patients, since 80–90% of them are diagnosed with advanced disease when the tumour is not resectable [6,7]. With the exception of the rare subset of mismatch repair-deficient tumours, checkpoint inhibitors have failed to show efficacy in metastatic patients. Under such circumstances, the solution possibly lies in early detection and proper classification of patients [4]. We describe and analyse the correspondence of most of the published molecular and metabolic signatures of PDAC and propose a modified metabolic signature that could stratify patients according to metabolic needs independently of the mutational load
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