PgmNr D1056: The Tumor Microenvironment And Mechanisms Governing Ras Tumor Overgrowth.

Authors:
Chiswili Yves Chabu 1,2 ; Tian Xu 1,2


Institutes
1) Yale University School Of Medicine, New Haven, CT; 2) Howard Hughes Medical Institute.


Keyword: other ( Oncogenic Ras )

Abstract:

We have been using Drosophila genetics to dissect the regulation of growth and metastasis, and have discovered conserved cell intrinsic and cell-cell signaling mechanisms within the tumor microenvironment. Here, I will discuss our recent findings of tumor-host and tumor-tumor signaling mechanisms promoting oncogenic Ras-mediated tumor overgrowth. First, we found that oncogenic Ras cells elevate the exocytosis of TNF to the surrounding wild-type cells, which consequently activate JNK signaling. This causes surrounding wild-type cells to secrete JAK-STAT ligands to activate JAK/STAT signaling in tumor cells and result in tumor overgrowth. Second, we discovered that oncogenic Ras signaling triggers the secretion of EGFR ligands. In turn, EGFR stimulates tumor overgrowth independent of the canonical Sos/Ras signaling pathway, but via ARF6. EGFR promotes ARF6 to control Hedgehog cellular transport in order to activate Hh signaling, which cooperates with oncogenic Ras to drive overgrowth.  Consistent with these studies, blocking secretion or ARF6 function inhibits the growth of oncogenic Ras-driven tumors in mammals. Collectively, these data highlight important cell-cell interactions within the tumor microenvironment and also explain both, the puzzling requirement of EGFR in some Ras cancers and the oncogenic cooperation between EGFR and Hh signaling.



Flybase Genetic Index:
1. FlyBase gene symbol: Ras85D; FBgn: 0003205
2. FlyBase gene symbol: Arf51F; FBgn: 0013750
3. FlyBase gene symbol: hh; FBgn: 0004644
4. FlyBase gene symbol: Egfr; FBgn: 0003731
5. FlyBase gene symbol: egr; FBgn: 0033483
6. FlyBase gene symbol: Stat92E; FBgn: 0016917