Abstract B26: A tumor specific molecular network promotes tumor growth by enforcing a JNK-YKI feed forward loop

Abstract

Abstract Cancer cells expand rapidly in response to altered cell-cell interactions among tumor and their surrounding cells; however, the molecular mechanisms by which alterations in these interactions promote aggressive metastatic tumor growth remain unclear. Earlier studies showed that increased oncogenic signaling and deregulation of inflammatory cytokines may be underlying tumor growth and progression. To study the nature of these interactions, we made mosaic clones expressing oncogenic forms of Yorkie (Yki) or Ras in polarity deficient cells (RasV12, scrib- or Yki3SA, scrib-) that are marked with GFP in Drosophila imaginal discs. This mosaic system recapitulates the clonal origins of human cancer and provides a distinct advantage in analyzing cell-cell (intratumoral and tumor-surrounding cell) interactions affecting tumor growth. Using these models of oncogenic cooperation, we show that tumor cells grow by activation of a previously unidentified network comprising Wingless (Wg), Dronc (Drosophila Caspase 9 ortholog), Jun N-terminal kinase (JNK), and Yki. Further, Toll-like receptor (TLR) component Cactus is highly expressed in the tumor cells. We show that Wg, Dronc, JNK, and Yki signaling are all required for the growth of tumors (RasV12, scrib-, and other tumor models), and downregulating Cactus affects both tumor progression and invasion. It is notable that Wg, Dronc, JNK, and Yki play a signaling and patterning role in normal development, and act as regulators of cell-cell interactions like cell competition and compensatory proliferation. JNK was previously shown to undergo a paradoxical signaling switch from proapoptosis to proproliferation that leads to activation of Yki. We report that Yki not only regulates the TLR component Cactus, but also positively regulates JNK in the tumor cells to form a JNK-Yki self-reinforcing positive feedback signal-amplification loop downstream of Wg and Dronc. We further demonstrate that the Wg-Dronc-JNK-Yki signaling network promotes tumor growth in other contexts of oncogenic cooperation. Overall, the identification of the Wg-Dronc-Yki-JNK molecular network and the organization of the signaling elements provide novel insights into how altered cell-cell interactions and signaling promote tumorigenesis. Our findings suggest that identification of molecular networks may provide significant insights about the key biologically meaningful changes in signaling pathways and paradoxical signals that promote tumorigenesis. Citation Format: Madhuri Kango-Singh. A tumor specific molecular network promotes tumor growth by enforcing a JNK-YKI feed forward loop [abstract]. In: Proceedings of the AACR Special Conference on the Hippo Pathway: Signaling, Cancer, and Beyond; 2019 May 8-11; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(8_Suppl):Abstract nr B26.