Using Drosophila to uncover the role of organismal physiology and the tumor microenvironment in cancer.

Cancer metastasis causes over 90% of cancer patient fatalities. Poor prognosis is determined by tumor type, the tumor microenvironment (TME), organ-specific biology, and animal physiology. While model organisms do not fully mimic the complexity of humans, many processes can be studied efficiently owing to the ease of genetic, developmental, and cell biology studies.

The transcription factor Xrp1 orchestrates both reduced translation and cell competition upon defective ribosome assembly or function.

Ribosomal Protein () gene haploinsufficiency affects translation rate, can lead to protein aggregation, and causes cell elimination by competition with wild type cells in mosaic tissues. We find that the modest changes in ribosomal subunit levels observed were insufficient for these effects, which all depended on the AT-hook, bZip domain protein Xrp1. Xrp1 reduced global translation through PERK-dependent phosphorylation of eIF2α.

spn-A/rad51 mutant exhibits enhanced genomic damage, cell death and low temperature sensitivity in somatic tissues.

Homologous recombination (HR) is one of the key pathways to repair double-strand breaks (DSBs). Rad51 serves an important function of catalysing strand exchange between two homologous sequences in the HR pathway. In higher organisms, rad51 function is indispensable with its absence leading to early embryonic lethality, thus precluding any mechanistic probing of the system.

Genome Damage Sensing Leads to Tissue Homeostasis in Drosophila.

DNA repair is a critical cellular process required for the maintenance of genomic integrity. It is now well appreciated that cells employ several DNA repair pathways to take care of distinct types of DNA damage. It is also well known that a cascade of signals namely DNA damage response or DDR is activated in response to DNA damage which comprise cellular responses, such as cell cycle arrest, DNA repair and cell death, if the damage is irreparable.

A potential link between p53, cell competition and ribosomopathy in mammals and in Drosophila.

The term cell competition has been used to describe the phenomenon whereby particular cells can be eliminated during tissue growth only when more competitive cells are available to replace them. Multiple examples implicate differential activity of p53 in cell competition in mammals, but p53 has not been found to have the same role in Drosophila, where the phenomenon of cell competition was first recognized. Recent studies now show that Drosophila cells harboring mutations in Ribosomal protein (Rp) genes, which are eliminated by cell competition with wild type cells, activate a p53 target gene, Xrp1.

The initiator caspase Dronc plays a non-apoptotic role in promoting DNA damage signalling in .

The phosphorylation of the variant histone H2Ax (denoted γH2Ax; γH2Av in flies) constitutes an important signalling event in DNA damage sensing, ensuring effective repair by recruiting DNA repair machinery. In contrast, the γH2Av response has also been reported in dying cells, where it requires activation of caspase-activated DNases (CADs). Moreover, caspases are known to be required downstream of DNA damage for cell death execution.