Simona Chera: Islet cell identity and diabetes development
Diabetes mellitus represents a group of energy metabolism diseases defined by chronically increased blood sugar levels (hyperglycemia) triggered by the inability of the body to produce and/or use sufficient insulin. Insulin is a hormone synthetized by the β-cells, which reside in the pancreatic islets alongside several other mono-hormonal endocrine cell types (islet non-β-cells). The contribution of these neighboring cells’ identity maintenance errors or altered proportions to diabetes development is unknown. We plan to bridge this knowledge gap by using novel mouse and human models of monogenic diabetes. In vivo analysis of these setups identified errors in islet non-β-cells identity maintenance, characterizing the contexts of overt diabetes.
Nils Halberg: Epigenetic Control of Obesity-induced Tumor Initiation
Epidemiological studies have established a positive association between obesity and the incidence of postmenopausal breast cancer. Moreover, it is known that obesity promotes stem cell-like properties of breast cancer cells. However, the cancer cell-autonomous mechanisms underlying this correlation are not well defined. Here we demonstrate that obesity-associated tumor formation is driven by cellular adaptation rather than expansion of pre-existing clones within the cancer cell population. While there is no correlation with specific mutations, cellular adaptation to obesity is governed by palmitic acid (PA) and leads to enhanced tumor formation capacity of breast cancer cells. This process is governed epigenetically through increased chromatin occupancy of the transcription factor CCAAT/enhancer-binding protein beta (C/EBPB). Obesity-induced epigenetic activation of C/EBPB regulates cancer stem-like properties by modulating the expression of key downstream regulators including CLDN1 and LCN2. Collectively, our findings demonstrate that obesity drives cellular adaptation to PA drives tumor initiation in the obese setting through activation of a C/EBPB dependent transcriptional network.