Patients with pancreatic cancer often battle cachexia, a devastating condition that causes extreme weight and muscle loss. Despite its severity, cachexia remains without a cure. Supported by the Marie Skłodowska-Curie Actions programme, the CAFinCAC project aims to change that. By focusing on fibroblasts (non-cancerous cells in pancreatic tumours known to influence cancer growth), my project is uncovering how these cells may also drive cachexia. Using advanced mouse models and insights into how cancer mutations alter fibroblast behaviour, the project hopes to pinpoint new therapeutic targets. This research could bring relief to patients beyond pancreatic cancer, offering hope where none currently exists.
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with high metastasis and therapeutic resistance. Activating Transcription Factor 4 (ATF4), a master regulator of cellular stress, is exploited by cancer cells to survive. My work and prior research provides evidence that high ATF4 expression correlates with worse overall survival in PDAC patients. Tomatidine, a natural steroidal alkaloid, is associated with inhibition of ATF4 signaling in multiple diseases. We discovered in vitro and in vivo tomatidine treatment of PDAC cells inhibits tumor growth. Tomatidine inhibited nuclear translocation of ATF4 and reduced the transcriptional binding of ATF4 with downstream promoters. Tomatidine enhanced gemcitabine chemosensitivity in 3D ECM-hydrogels and in orthotopic model of pancreatic cancer in vivo. Tomatidine treatment was associated with induction of ferroptosis signaling validated by increased lipid peroxidation, mitochondrial respiratory capacity and decreased GPX4 expression in PDAC cells. My dissertation research highlights a possible therapeutic approach utilizing a plant derived metabolite, tomatidine, to target ATF4 activity in PDAC.
Chronic inflammatory disorders such as pancreatitis are hard to tackle and can give rise to carcinogenesis. Using dietary interventions with foods possessing anti-inflammatory metabolites can be an approach to address pancreatitis. Dr. Mace’s laboratory is investigating the role of bioactive foods such as soy and tomatoes to determine how they modulate chronic inflammation and carcinogenesis. Recently, we discovered that a novel soy-tomato intervention can reduce inflammation and disease severity in a pre-clinical model of chronic pancreatitis.
Sepsis is a condition marked by systemic response to infection affecting multiple organs. In sepsis, the pro-inflammatory genes are epigenetically silenced due to increase in DNA methyl transferase (DNMT) expression levels. This leads to reduced immune response of the patients resulting in poor prognosis and relapse. Knowledge about how these epigenetic signatures is transferred from site of sepsis to distant recipient cells will enable proper treatment approaches. One potential way of this transfer could be through the involvement of extracellular vesicles (EVs). EVs are small, spherical lipid bilayer packages consisting of organelle free cytosol, nucleic acids and protein released by donor cells into the extracellular environment to be taken up by recipient cells. These vesicles can modulate host immune responses executing both pro-inflammatory and anti-inflammatory reactions through the cargo packaged in them. The objective of my study in Dr. Chandan Sen’s lab at OSU as a Khorana Program scholar was to assess if the presence of epigenetic modifiers in the EVs can modulate the disease and to analyze whether the inhibition of uptake mechanisms of EVs is reflected in reduced spread of the infection, further assessing the effective mode of inhibition. The results demonstrated epigenetic modifiers produced during sepsis conditions and packaged in EVs have a role in progression of the infection to multiple organs and inhibitors to EV uptake mechanisms can therefore be used to control sepsis.
A major problem in studying human brain diseases is the inaccessibility of viable diseased tissue. Induced pluripotent stem cells (iPSCs) and their application as human disease cell model can be exploited in this regard. Loss-of-function mutations in disease genes can be recapitulated by Cre recombinase mediated genetic deletions. As a Masters’ thesis student in Dr, Ulrike Nuber’s lab in TU Darmstadt. Germany, I worked to evaluate the functionality of different neural cell specific promoters. To achieve cell type-specific gene deletions, I developed a system that was able to produce different signals in presence and absence of Cre to evaluate the functionality of different neural cell promoters visually under the fluorescent microscope. Further, the system was verified at the genomic level through genotyping. The results found were helpful in successful understanding of the functionality of these vectors and used for iPSC disease modelling.