Afroditi Petsakou, Ph.D.

We aim to understand how the crosstalk between the nervous and intestinal system restores tissue homeostasis and prevents diseases. We are interested in identifying key neuro-regulated mechanisms that help the gut heal after injury and prevent the development of chronic intestinal disorders like inflammatory bowel diseases and cancer. Our studies address three basic unanswered questions:

1. Which mechanisms tilt the scales between wound healing and tumorigenesis?
   A fundamental unresolved question in regeneration is how a tissue returns to homeostasis after injury. Answering this question is vital not only for understanding how to heal tissues but also to protect against systemic effects that could worsen disease progression in complex disorders like cancer. Previously, we discovered that in the fly gut, Ca2+ currents across the intestinal epithelium promote homeostasis after injury, while loss of these epithelial Ca2+ currents promotes ISC over-proliferation and makes the gut prone to hyperplasia. By combining fly genetics and mouse intestinal organoids, together with advanced microscopy, high-resolution multiplexed immunofluorescence, and multi-omic approaches, we will unravel downstream ion channels, pumps, and exchangers that guide conserved molecular pathways towards either wound healing or tumorigenesis.
2. How do peripheral neurons impact intestinal tumor growth?
   How peripheral neurons impact cancer progression is a vital unresolved question in cancer neuroscience. It is proposed that the tumor microenvironment reprograms the function of peripheral neurons, but the underlying mechanisms remain unclear. Previously, we characterized a specific small population of cholinergic enteric neurons in the fly, which we named ARCENs (Anti-inflammatory Recovery Specific Enteric Neurons), that sense inflammatory cytokines and, in response, promote rapid repair of the intestinal epithelium and transition to homeostasis after injury. We will take advantage of the direct signaling between ARCENs and the gut, using it as a simple in vivo bidirectional model to identify fundamental mechanisms governing neuro-gut communication during tumor development. Utilizing the powerful genetic toolkit available in Drosophila, we will perform sophisticated thermo- and opto-genetic perturbations and perform spatial transcriptomics to identify neuronal changes during intestinal tumor growth. Overall, we will unravel basic mechanisms used by the gut tumor microenvironment to hijack the function of peripheral neurons.
3. How do changes in feeding behavior alter cancer progression?
   Cancer cachexia (CC) is a complex, lethal syndrome characterized by organ wasting. Having a comprehensive understanding of the early events before the onset of organ wasting is crucial for the etiology and diagnosis of this syndrome.  Anorexia (loss of appetite) is an early sign of CC; however, early CC-linked mechanisms responsible for changes in feeding behavior remain unclear. We previously discovered that inflammation and low insulin signaling impair feeding pathways in the fly brain and cause early appetite changes, making the fly prone to protein malnutrition, which worsens organ wasting. Building on these findings, we will utilize Drosophila, which is a powerful system to study organ communication, tumor growth, and feeding behavior, to decipher how mechanisms driving amino-acid feeding imbalance guide early aspects of organ wasting that could be used as potential diagnostic markers and therapeutic targets.

1. Petsakou, A.*, Filine. E., Li, M., Chen, Y., Zheng, A., and Perrimon, N*. Tumor-induced orexigenic imbalance lowers protein appetite and drives early organ wasting symptoms. Nature Communications  DOI:10.1038/s41467-026-70074-2 (2026). (*corresponding author)
2. Lane, E.A., Petsakou, A., Liu, Y., Chen, W., Qadiri, M., Hu, Y., and Perrimon, N. Cholinergic signaling modulates intestinal pathophysiology in a Drosophila model of cystic fibrosis. PLOS Genetics 22, e1012048, DOI:10.1371/journal.pgen.1012048. (2026).
3. Petsakou, A.*, Liu, Y., Liu, Y., Comjean, A., Hu, Y., and Perrimon, N*. Cholinergic neurons trigger epithelial Ca(2+) currents to heal the gut. Nature 623, 122-131. DOI: 10.1038/s41586-023-06627-y. (2023). (*corresponding author)
4. Petsakou, A.*, and Perrimon, N*. Bioelectric regulation of intestinal stem cells. Trends in Cell Biology DOI: 10.1016/j.tcb.2022.10.003. (2023). (*corresponding author)
5. Petsakou, A., and Perrimon, N. No sugar, just protein, please - says the fly. Nature Metabolism 4, 1436-1437. DOI: 10.1038/s42255-022-00665-y. (2022).
6. Petsakou, A., and Perrimon, N. "ISN't Thirst Sweet?" Says the Fly. Cell 166, 796-797. DOI: 10.1016/j.cell.2016.07.038. (2016).
7. Petsakou, A., Sapsis, T.P., and Blau, J. Circadian Rhythms in Rho1 Activity Regulate Neuronal Plasticity and Network Hierarchy. Cell 162, 823-835. DOI: 10.1016/j.cell.2015.07.010. (2015).