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.

Homozygosity for lethal(2)giant larvae (lgl), a mutation in a tumor suppressor gene of Drosophila, induces neoplasia of the imaginal discs. To explore the developmental capacities of lgl mutant cells, we have investigated their growth and differentiation in genetic mosaics. Adult wings mosaic for lgl displayed abnormal growth and differentiation of the lgl mutant and neighboring wild-type cells, suggesting aberrant cell-cell interactions during development. lgl mutant clones also straddled the anteroposterior boundary of the wing imaginal disc, apparently due to failure of the cells of the anterior and the posterior compartment to segregate at the boundary. To further test if anteroposterior compartmentalization takes place in the neoplastic imaginal discs of lgl mutant larvae, we studied the expression of an engrailed (en)-specific lacZ reporter gene during progressive stages of their tumorous growth. Our results show that en is activated in the posterior compartments of the neoplastic imaginal discs. However, during later stages of tumorous overgrowth, the en-expressing and nonexpressing cells appear to show extensive intermixing. These observations suggest that neoplastic transformation of imaginal discs involves loss of their normal cell-cell interactions and signaling.

In this paper, we establish the existence of both compressive stress and charge transfer Lattice strain estimated from XRD peaks are correlated to the observed Raman shift.

Lethal mutations in the giant discs (lgd) and fat (ft) tumor suppressor genes of Drosophila cause epithelial hyperplasia in all imaginal discs. By contrast, mutations in the vestigial (vg) gene adversely affect cell viability in the wing imaginal discs and consequently cause loss of pattern in the adult wings. However, combining homozygous lgd or ft mutations with homozygous vg1 increases the size of the wing imaginal discs and partially restores the bristle pattern in the wings of pharate adults. Comparable pattern restoration in vg1 wings is also induced by a newly isolated weak hypomorphic lgd3 allele. Further, mosaic analysis revealed that whereas lgd clones generated by the Minute technique display abnormal differentiation, those induced in a homozygous vg1 background exhibit autonomous restoration of wing pattern. These results suggest that pattern restoration in vg1 wings can serve as an assay for hyperplasia induced by mutations in Drosophila tumor suppressor genes.

The Notch (N) signalling pathway is recruited for segregation of cell fates in a number of Drosophila tissue types. We show here that N dependent segmentation of Drosophila legs is regulated by a dynamic pattern of expression of its ligand, DELTA (DL). During third larval instar and early stages of pupation, high levels of DL expression is seen in stripes of cells in the leg imaginal discs which later form the proximal borders of leg joints. These domains also displayed heightened Dl enhancer activity. During subsequent stages of pupation, following segmentation of the leg primordium, DL expression becomes uniform throughout these segments barring the joints. We further show that regulatory Dl mutations or mis-expression of DL abolish leg segmentation. Domains of N signalling for segmentation of legs of flies are thus set up by a stringent spatial regulation of expression of its ligand at the segment border. Further, a comparable role of DL in antennal development reveals a common paradigm of DL-N signalling for segmentation of appendages in flies.