Cytoneme-mediated signaling essential for tumorigenesis

Abstract

Communication between neoplastic cells and cells of their microenvironment is critical to cancer progression. To investigate the role of cytoneme-mediated signaling as a mechanism for distributing growth factor signaling proteins between tumor and tumor-associated cells, we analyzed EGFR and RET Drosophila tumor models and tested several genetic loss-of-function conditions that impair cytoneme-mediated signaling. Neuroglian, capricious, Irk2, SCAR, and diaphanous are genes that cytonemes require during normal development. Neuroglian and Capricious are cell adhesion proteins, Irk2 is a potassium channel, and SCAR and Diaphanous are actin-binding proteins, and the only process to which they are known to contribute jointly is cytoneme-mediated signaling. We observed that diminished function of any one of these genes suppressed tumor growth and increased organism survival. We also noted that EGFR-expressing tumor discs have abnormally extensive tracheation (respiratory tubes) and ectopically express Branchless (Bnl, a FGF) and FGFR. Bnl is a known inducer of tracheation that signals by a cytoneme-mediated process in other contexts, and we determined that exogenous over-expression of dominant negative FGFR suppressed tumor growth. Our results are consistent with the idea that cytonemes move signaling proteins between tumor and stromal cells and that cytoneme-mediated signaling is required for tumor growth and malignancy.

Neuronal signatures in cancer

“…In drosophila, specialized neurite-like protrusions called cytonemes have been described during tissue development 38,39 and tumorigenesis. 40 Similar to TMs and neurites, glutamatergic synapses on cytonemes induce intracellular calcium transients. 41 Finally, even in brain metastasis, only a minority of cells manages to colonize the brain, 42 and these cells are genomically distinct from extracranial metastases, 43 suggesting that certain preexisting expression profiles of cancers might promote brain colonization.…”

Regulated delivery controls Drosophila Hedgehog, Wingless and Decapentaplegic signaling

“…Hh BAC (Chen et al, 2017), Dpp BAC (this study), Dpp:Cherry crispr (Fereres et al, 2019), wg-gal4 (Giráldez et al, 2002), 1151-gal4 (Roy and VijayRaghavan, 1997), UAS-Wg:GFP (Pfeiffer et al, 2002), UAS-mcd8:GFP (Roy et al, 2011), btl-LHG (Roy et al, 2014), lexOcherry:CAAX (K. Basler), UAS-Cut, UAS-btl DN (Reichman-Fried and Shilo, 1995), UAS-mskRNAi (Bloomington #27572) Dpp BAC: BAC clone CH321-23O18 (CHORI) was inserted into cytological location 65B2 (Venken et al, 2009).…”

Hedgehog produced by the Drosophila wing imaginal disc induces distinct expression responses in three target tissues

“…Further analysis of the elements that regulate ct and aop will be necessary to understand the basis for the combinatorial regulation. (Tanimoto et al, 2000), Ay-Gal4 (Bloomington#3953), btl-LHG (Roy et al, 2014), 1151-Gal4 (Roy and VijayRaghavan, 1997); UAS lines: UAS-mcd8:GFP (Roy et al, 2011), UAS-mcd8:Cherry (Roy et al, 2011), UAS-Ptc (Johnson et al, 1995), UAS-Ptc loop2 (Briscoe et al, 2001), UAS-SmoRNAi (VDRC#9542), UAS-enRNAi (Bloomington #33715), UAS-Hh:GFP (Torroja et al, 2004), UAS-CD4:mIFP (Yu et al, 2015), UAS-CD4:GFP1-10 (from Kristen Scott), UAS-SCAR-RNAi (VDRC#21908), UAS-disp RNAi (Bloomington#27247), UAS-dia-RNAi (Bloomington), UAS-hhRNAi (Bloomington#31475), UAS-Btl:Cherry (Roy et al, 2011), UAS-Ptc:GFP (Torroja et al, 2004); LexO lines: lexO-CD2:GFP (Torroja et al, 2004), lexO-CD4:GFP 11 (Roy et al, 2014), lexO-n-syb-GFP 11 (Macpherson et al, 2015), lexO-diaRNAi (Fereres et al, 2019), lexO-cherry:CAAX (from K. Basler); BAC/Crispr/Fosmid Knock-in lines:…”