Interaction between RasV12 and scribble clones induces tumour growth and invasion

Human tumours have a large degree of cellular and genetic heterogeneity. Complex cell interactions in the tumour and its microenvironment are thought to have an important role in tumorigenesis and cancer progression. Furthermore, cooperation between oncogenic genetic lesions is required for tumour development; however, it is not known how cell interactions contribute to oncogenic cooperation. The genetic techniques available in the fruitfly Drosophila melanogaster allow analysis of the behaviour of cells with distinct mutations, making this the ideal model organism with which to study cell interactions and oncogenic cooperation. In Drosophila eye-antennal discs, cooperation between the oncogenic protein RasV12 (ref. 5) and loss-of-function mutations in the conserved tumour suppressor scribbled (scrib) gives rise to metastatic tumours that display many characteristics observed in human cancers. Here we show that clones of cells bearing different mutations can cooperate to promote tumour growth and invasion in Drosophila. We found that the RasV12 and scrib- mutations can also cause tumours when they affect different adjacent epithelial cells. We show that this interaction between RasV12 and scrib- clones involves JNK signalling propagation and JNK-induced upregulation of JAK/STAT-activating cytokines, a compensatory growth mechanism for tissue homeostasis. The development of RasV12 tumours can also be triggered by tissue damage, a stress condition that activates JNK signalling. Given the conservation of the pathways examined here, similar cooperative mechanisms could have a role in the development of human cancers.

[1]  N. Perrimon,et al.  Drosophila unpaired encodes a secreted protein that activates the JAK signaling pathway. , 1998, Genes & development.

[2]  H. Dvorak.  Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. , 1986, The New England journal of medicine.

[3]  Hyung Don Ryoo,et al.  Apoptotic cells can induce compensatory cell proliferation through the JNK and the Wingless signaling pathways. , 2004, Developmental cell.

[4]  G. Morata,et al.  Apoptosis in Drosophila: compensatory proliferation and undead cells. , 2009, The International journal of developmental biology.

[5]  Stephen Brown,et al.  Identification of the first invertebrate interleukin JAK/STAT receptor, the Drosophila gene domeless , 2001, Current Biology.

[6]  Norbert Perrimon,et al.  Signaling role of hemocytes in Drosophila JAK/STAT-dependent response to septic injury. , 2003, Developmental cell.

[7]  J. C. Pastor-Pareja,et al.  Intrinsic tumor suppression and epithelial maintenance by endocytic activation of Eiger/TNF signaling in Drosophila. , 2009, Developmental cell.

[8]  Alberto Mantovani,et al.  Inflammation and cancer: back to Virchow? , 2001, The Lancet.

[9]  Tian Xu,et al.  A Genetic Screen in Drosophila for Metastatic Behavior , 2003, Science.

[10]  Z. Xuan,et al.  Deregulation of Scribble Promotes Mammary Tumorigenesis and Reveals a Role for Cell Polarity in Carcinoma , 2008, Cell.

[11]  A. Martinez-Arias,et al.  puckered encodes a phosphatase that mediates a feedback loop regulating JNK activity during dorsal closure in Drosophila. , 1998, Genes & development.

[12]  D. Hanahan,et al.  The Hallmarks of Cancer , 2000, Cell.

[13]  D. Bohmann,et al.  JNK‐ and Fos‐regulated Mmp1 expression cooperates with Ras to induce invasive tumors in Drosophila , 2006, The EMBO journal.

[14]  K. Kinzler,et al.  Lessons from Hereditary Colorectal Cancer , 1996, Cell.

[15]  E. Martín-Blanco,et al.  JNK signaling pathway required for wound healing in regenerating Drosophila wing imaginal discs. , 2005, Developmental biology.

[16]  J. C. Pastor-Pareja,et al.  Adaptive genetic variation, stress and glucose regulation , 2008, Disease Models & Mechanisms.

[17]  E. F. ARMSTRONG,et al.  Annual Review of Biochemistry , 1944, Nature.

[18]  H. Jasper,et al.  Non-cell-autonomous induction of tissue overgrowth by JNK/Ras cooperation in a Drosophila tumor model. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[19]  H. Richardson,et al.  scribble mutants cooperate with oncogenic Ras or Notch to cause neoplastic overgrowth in Drosophila , 2003, The EMBO journal.

[20]  G M Rubin,et al.  Ectopic expression of activated Ras1 induces hyperplastic growth and increased cell death in Drosophila imaginal tissues. , 1998, Development.

[21]  I. Hariharan,et al.  Regulation of imaginal disc growth by tumor-suppressor genes in Drosophila. , 2006, Annual review of genetics.

[22]  N. Perrimon,et al.  GFP reporters detect the activation of the Drosophila JAK/STAT pathway in vivo. , 2007, Gene expression patterns : GEP.

[23]  Stephen Brown,et al.  Characterisation of Upd2, a Drosophila JAK/STAT pathway ligand. , 2005, Developmental biology.

[24]  G. Rubin,et al.  Analysis of genetic mosaics in developing and adult Drosophila tissues. , 1993, Development.

[25]  M. Barbacid.  ras genes. , 1987, Annual review of biochemistry.

[26]  T. Igaki,et al.  Loss of Cell Polarity Drives Tumor Growth and Invasion through JNK Activation in Drosophila , 2006, Current Biology.

[27]  N. Perrimon,et al.  The roles of the Drosophila JAK/STAT pathway , 2000, Oncogene.

[28]  J. C. Pastor-Pareja,et al.  Basement membrane remodeling is essential for Drosophila disc eversion and tumor invasion , 2007, Proceedings of the National Academy of Sciences.

[29]  N. Perrimon,et al.  Localization of apical epithelial determinants by the basolateral PDZ protein Scribble , 2000, Nature.

[30]  L. Coussens,et al.  Paradoxical roles of the immune system during cancer development , 2006, Nature Reviews Cancer.