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Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related mortality among adults in developed countries. The discovery of the most common genetic alterations as well as the development of organoid models of pancreatic cancer have provided insight into the fundamental pathways driving tumor progression from a normal cell to non-invasive precursor lesion and finally to widely metastatic disease, offering new opportunities for identifying the key driver of cancer evolution. Obesity is one of the most serious public health challenges of the 21st century. Several epidemiological studies have shown the positive association between obesity and cancer-related morbidity/mortality, as well as poorer prognosis and treatment outcome. Despite strong evidence indicates a link between obesity and cancer incidence, the molecular basis of the initiating events remains largely elusive. This is mainly due to the lack of an accurate and reliable model of pancreatic carcinogenesis that mimics human obesity-associated PDAC, making data interpretation difficult and often confusing. Here we propose a feasible and manageable organoid-based preclinical tool to study the effects of obesity on pancreatic carcinogenesis. Therefore, we tracked the effects of obesity on the natural evolution of PDAC in a genetically defined transplantable model of the syngeneic murine pancreatic preneoplastic lesion (mP) and tumor (mT) derived-organoids that recapitulates the progression of human disease from early preinvasive lesions to metastatic disease. Our results suggest that organoid-derived transplant in obese mice represents a suitable system to study early steps of pancreatic carcinogenesis and supports the hypothesis that inflammation induced by obesity stimulates tumor progression and metastatization during pancreatic carcinogenesis.
Highlights
Cancer and obesity are the two major epidemics of the 21st century (Kaidar-Person et al, 2011)
We recently demonstrated that factors secreted by adipocytes induced epithelial-to-mesenchymal transition (EMT) and increased aggressiveness in two pancreatic cell transformation model system by orchestrating a complex paracrine signaling of soluble modulators of the non-canonical WNT signaling pathway that impinges upon activation and nuclear translocation of WNT receptor ROR2 (Carbone et al, 2018)
For identification purposes the samples were subjected to a data dependent acquisition (DDA): the mass spectrometer analysis was performed using a mass range of 100–1500 Da (TOF scan with an accumulation time of 0.25 s), followed by a MS/MS product ion scan from 200 to 1250 Da with the abundance threshold set at 30 cps (35 candidate ions can be monitored during every cycle)
Summary
Cancer and obesity are the two major epidemics of the 21st century (Kaidar-Person et al, 2011). Preclinical evidence indicated that a “sensitizer” background ( oncogenic Kras activation) is a necessary prerequisite when trying to identify factors (genetic or nongenetic) that accelerate progression of pancreatic cancer in mouse models (Perez-Mancera et al, 2012) where genes’ inactivation due to sleeping beauty transpositions was not sufficient to drive tumor formation in the absence of Kras activation. This reflects on the nearly universal Kras mutation in PDAC and the well-established consensus that oncogenic mutation of Kras is the initiating event in pancreatic carcinogenesis. We tracked the effects of obesity on the natural evolution of PDAC in a genetically defined transplantable model of syngeneic murine pancreatic preneoplastic (mP) and tumoural (mT) derived organoids that recapitulates the progression of the human disease from early preinvasive lesions to metastatic disease
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