Cell polarity opposes Jak/STAT-mediated Escargot activation that drives intratumor heterogeneity in a Drosophila tumor model

• Published in: Cell reports (Cambridge) 2023-02, Vol.42 (2), p.112061-112061, Article 112061
• Main Authors: Chatterjee, Deeptiman, Cong, Fei, Wang, Xian-Feng, Machado Costa, Caique Almeida, Huang, Yi-Chun, Deng, Wu-Min
• Format: Article
• Language: English
• Subjects: CP: Cancer; depolyploidization; Drosophila tumor model; epithelial polarity; intratumor heterogeneity; Jak/STAT signaling; paracrine signaling; single-cell RNA sequencing; stem cell plasticity; transcriptomics; tumorigenesis
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2023.112061

In proliferating neoplasms, microenvironment-derived selective pressures promote tumor heterogeneity by imparting diverse capacities for growth, differentiation, and invasion. However, what makes a tumor cell respond to signaling cues differently from a normal cell is not well understood. In the Drosophila ovarian follicle cells, apicobasal-polarity loss induces heterogeneous epithelial multilayering. When exacerbated by oncogenic-Notch expression, this multilayer displays an increased consistency in the occurrence of morphologically distinguishable cells adjacent to the polar follicle cells. Polar cells release the Jak/STAT ligand Unpaired (Upd), in response to which neighboring polarity-deficient cells exhibit a precursor-like transcriptomic state. Among the several regulons active in these cells, we could detect and further validate the expression of Snail family transcription factor Escargot (Esg). We also ascertain a similar relationship between Upd and Esg in normally developing ovaries, where establishment of polarity determines early follicular differentiation. Overall, our results indicate that epithelial-cell polarity acts as a gatekeeper against microenvironmental selective pressures that drive heterogeneity. [Display omitted] •Cell-polarity loss in Drosophila follicle cells forms heterogeneous multilayers•Spatially restricted Jak/STAT ligand Unpaired activates Escargot in adjacent cells•Escargot activation induces ploidy heterogeneity, likely via depolyploidization•Upd exposure decides phenotypic plasticity in both tumorigenesis and development Chatterjee et al. show that in Drosophila ovaries, loss of epithelial-cell polarity causes heterogeneous multilayering, where exposure to Jak/STAT ligand Upd activates Esg in polarity-deficient cells that are maintained at developmental immaturity. Cell polarity is identified as a barrier against Upd-mediated Esg activation, which is also observed in normal development.