Incidence of pancreatic cancer is dramatically increased by a high fat, high calorie diet in KrasG12D mice.

Epidemiologic data has linked obesity to a higher risk of pancreatic cancer, but the underlying mechanisms are poorly understood. To allow for detailed mechanistic studies in a relevant model mimicking diet-induced obesity and pancreatic cancer, a high-fat, high-calorie diet (HFCD) was given to P48+/Cre;LSL-KRASG12D (KC) mice carrying a pancreas-specific oncogenic Kras mutation. The mice were randomly allocated to a HFCD or control diet (CD). Cohorts were sacrificed at 3, 6, and 9 months and tissues were harvested for further analysis. Compared to CD-fed mice, HFCD-fed animals gained significantly more weight. Importantly, the cancer incidence was remarkably increased in HFCD-fed KC mice, particularly in male KC mice. In addition, KC mice fed the HFCD showed more extensive inflammation and fibrosis, and more advanced PanIN lesions in the pancreas, compared to age-matched CD-fed animals. Interestingly, we found that the HFCD reduced autophagic flux in PanIN lesions in KC mice. Further, exome sequencing of isolated murine PanIN lesions identified numerous genetic variants unique to the HFCD. These data underscore the role of sustained inflammation and dysregulated autophagy in diet-induced pancreatic cancer development and suggest that diet-induced genetic alterations may contribute to this process. Our findings provide a better understanding of the mechanisms underlying the obesity-cancer link in males and females, and will facilitate the development of interventions targeting obesity-associated pancreatic cancer

De novo designed library of linear helical peptides: An exploratory tool in the discovery of protein-protein interaction modulators

Protein-protein interactions (PPIs) have emerged as important targets for pharmaceutical intervention because of their essential role in numerous physiological and pathological processes, but screening efforts using small-molecules have led to very low hit rates. Linear peptides could represent a quick and effective approach to discover initial PPI hits, particularly if they have inherent ability to adopt specific peptide secondary structures. Here, we address this hypothesis through a linear helical peptide library, composed of four sublibraries, which was designed by theoretical predictions of helicity (Agadir software). The 13-mer peptides of this collection fixes either a combination of three aromatic or two aromatic and one aliphatic residues on one face of the helix (Ac-SSEEX5ARNX9AAX12N-NH 2), since these are structural features quite common at PPIs interfaces. The 81 designed peptides were conveniently synthesized by parallel solid-phase methodologies, and the tendency of some representative library components to adopt the intended secondary structure was corroborated through CD and NMR experiments. As proof of concept in the search for PPI modulators, the usefulness of this library was verified on the widely studied p53-MDM2 interaction and on the communication between VEGF and its receptor Flt-1, two PPIs for which a hydrophobic α-helix is essential for the interaction. We have demonstrated here that, in both cases, selected peptides from the library, containing the right hydrophobic sequence of the hot-spot in one of the protein partners, are able to interact with the complementary protein. Moreover, we have discover some new, quite potent inhibitors of the VEGF-Flt-1 interaction, just by replacing one of the aromatic residues of the initial F5Y 9Y12 peptide by W, in agreement with previous results on related antiangiogenic peptides. Finally, the HTS evaluation of the full collection on thermoTRPs has led to a few antagonists of TRPV1 and TRPA1 channels, which open new avenues on the way to innovative modulators of these channels.Peer Reviewe

Incidence of pancreatic cancer is dramatically increased by a high fat, high calorie diet in KrasG12D mice

<div><p>Epidemiologic data has linked obesity to a higher risk of pancreatic cancer, but the underlying mechanisms are poorly understood. To allow for detailed mechanistic studies in a relevant model mimicking diet-induced obesity and pancreatic cancer, a high-fat, high-calorie diet (HFCD) was given to <i>P48</i>^<i>+/Cre</i><i>;LSL-KRAS</i>^<i>G12D</i> (KC) mice carrying a pancreas-specific oncogenic Kras mutation. The mice were randomly allocated to a HFCD or control diet (CD). Cohorts were sacrificed at 3, 6, and 9 months and tissues were harvested for further analysis. Compared to CD-fed mice, HFCD-fed animals gained significantly more weight. Importantly, the cancer incidence was remarkably increased in HFCD-fed KC mice, particularly in male KC mice. In addition, KC mice fed the HFCD showed more extensive inflammation and fibrosis, and more advanced PanIN lesions in the pancreas, compared to age-matched CD-fed animals. Interestingly, we found that the HFCD reduced autophagic flux in PanIN lesions in KC mice. Further, exome sequencing of isolated murine PanIN lesions identified numerous genetic variants unique to the HFCD. These data underscore the role of sustained inflammation and dysregulated autophagy in diet-induced pancreatic cancer development and suggest that diet-induced genetic alterations may contribute to this process. Our findings provide a better understanding of the mechanisms underlying the obesity-cancer link in males and females, and will facilitate the development of interventions targeting obesity-associated pancreatic cancer.</p></div

HFCD leads to greater weight gain in male and female KC mice.

<p><b>(A)</b> A schematic view of the study design. <b>(B)</b> Weight gain of male (left panel) and female (right panel) KC mice fed the CD or HFCD. The values are means ± SD. *<i>P</i><0.05, Student’s <i>t</i>-tests. For the male mice collected at 3, 6, and 9 months, n = 12 (5 on CD and 7 on HFCD), 12 (6 on CD and 6 on HFCD), and 11 (5 on CD and 6 on HFCD), respectively. For the female mice collected at 3, 6, and 9 months, n = 11 (6 on CD and 5 on HFCD), 12 (5 on CD and 7 on HFCD), and 11 (5 on CD and 6 on HFCD), respectively. <b>(C)</b> Plasma levels of insulin, leptin, cholesterol, glucose, and triglycerides in 9-month-old KC mice fed the CD or HFCD. Data are depicted as means ± SD. *<i>P</i><0.05 vs. control, Student’s <i>t</i>-tests.</p

HFCD promotes inflammation in the pancreas of KC mice.

<p>Inflammatory parameters in the histological sections of pancreas were evaluated quantitatively. Specifically, acinar loss scores, inflammatory scores, fibrosis scores, and pancreatitis indices were determined for male and female KC mice fed the CD or HFCD for different time periods. The values are means ± SD. *<i>P</i><0.05, Student’s <i>t</i>-tests.</p