title: Epithelial neoplasia in Drosophila entails switch to primitive cell states.
abstract: Only select cell types in an organ display neoplasia when targeted oncogenically. How developmental lineage hierarchies of these cells prefigure their neoplastic propensities is not yet well-understood. Here we show that neoplastic Drosophila epithelial cells reverse their developmental commitments and switch to primitive cell states. In a context of alleviated tissue surveillance, for example, loss of Lethal giant larvae (Lgl) tumor suppressor in the wing primordium induced epithelial neoplasia in its Homothorax (Hth)-expressing proximal domain. Transcriptional profile of proximally transformed mosaic wing epithelium and functional tests revealed tumor cooperation by multiple signaling pathways. In contrast, lgl(-) clones in the Vestigial (Vg)-expressing distal wing epithelium were eliminated by cell death. Distal lgl(-) clones, however, could transform when both tissue surveillance and cell death were compromised genetically and, alternatively, when the transcription cofactor of Hippo signaling pathway, Yorkie (Yki), was activated, or when Ras/EGFR signaling was up-regulated. Furthermore, transforming distal lgl(-) clones displayed loss of Vg, suggesting reversal of their terminal cell fate commitment. In contrast, reinforcing a distal (wing) cell fate commitment in lgl(-) clones by gaining Vg arrested their neoplasia and induced cell death. We also show that neoplasia in both distal and proximal lgl(-) clones could progress in the absence of Hth, revealing Hth-independent wing epithelial neoplasia. Likewise, neoplasia in the eye primordium resulted in loss of Elav, a retinal cell marker; these, however, switched to an Hth-dependent primitive cell state. These results suggest a general characteristic of "cells-of-origin" in epithelial cancers, namely their propensity for switch to primitive cell states.
authors.affiliation: Department of Biological Sciences and Bioengineering, Indian Institute of Technology Kanpur, Kanpur 208 016, India.
authors.forename: Sumbul J
authors.initials: SJ
authors.lastname: Khan
authors.forename: Anjali
authors.initials: A
authors.lastname: Bajpai
authors.forename: Mohammad Atif
authors.initials: MA
authors.lastname: Alam
authors.forename: Ram P
authors.initials: RP
authors.lastname: Gupta
authors.forename: Sneh
authors.initials: S
authors.lastname: Harsh
authors.forename: Ravi K
authors.initials: RK
authors.lastname: Pandey
authors.forename: Surbhi
authors.initials: S
authors.lastname: Goel-Bhattacharya
authors.forename: Aditi
authors.initials: A
authors.lastname: Nigam
authors.forename: Arati
authors.initials: A
authors.lastname: Mishra
authors.forename: Pradip
authors.initials: P
authors.lastname: Sinha
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D002454:Cell Differentiation / Q000235:genetics*; D019070:Cell Lineage / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D029721:Drosophila Proteins / Q000235:genetics* / Q000378:metabolism; D004331:Drosophila melanogaster / Q000166:cytology / Q000235:genetics* / Q000254:growth & development; D004847:Epithelial Cells / Q000378:metabolism*; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008856:Microscopy, Fluorescence; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D014921:Wings, Animal / Q000166:cytology / Q000254:growth & development / Q000378:metabolism; D000091102:YAP-Signaling Proteins; D000099317:Hippo Kinases
chemical_list: D029721:Drosophila Proteins; D066246:ErbB Receptors; D049452:Green Fluorescent Proteins; D018398:Homeodomain Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases; D015534:Trans-Activators; D025521:Tumor Suppressor Proteins; D000091102:YAP-Signaling Proteins; C503814:Yki protein, Drosophila; C108704:hth protein, Drosophila; C081435:l(2)gl protein, Drosophila; C095064:vg protein, Drosophila; C499474:hpo protein, Drosophila; D000099317:Hippo Kinases