Cell and Tissue Signaling

Tuesday, October 18, 2005 3:00 PM-5:00 PM Exhibit Hall

(PP274) A C. elegans model of EGFR-mediated treatment resistance to cytotoxic therapy.

Weidhaas, Joanne*,1, Eisenmann, David2, 1 Therapeutic Radiology, New Haven, CT2

ABSTRACT- Purpose/Objective: Our goal has been to define the genetic mechanisms of EGFR-mediated cancer resistance in an intact animal system. We chose C. elegans as our model, with its advantages being that it is the simplest multicellular organism, is fully sequenced and has an EGFR-signaling pathway and a DNA damage response system that are highly conserved to humans. Materials & Methods: We began by creating a model of radiation-induced clonogenic cell death in the C. elegans vulva, a well-studied organ known to be primarily dependent on the EGFR-Ras/MAPK signaling pathway. Radiation was performed on synchronized worms using a Cs137 irradiator (Mark I Model 68), and radiation sensitivity was measured by scoring post-irradiation vulval abnormalities using Nomarski optics. In addition, we have created a model of accelerated repopulation (AR) in C. elegans. AR is the accelerated growth of tumor cells in response to cytotoxic treatment, and after radiotherapy has been linked to the EGFR-signaling pathway. Our AR model uses C. elegans strains harboring gain-of-function (GOF) mutations of the EGFR pathway, which have a multivulva (MUV) phenotype as a result of induction of accessory vulval cells, reminiscent of the uncontrolled cell proliferation caused by these same activating mutations in mammalian tumors. Results/Conclusions: We found that both the DNA damage response (DDR) pathway and the EGFR-Ras/MAPK pathway are necessary for protection from radiation induced clonogenic cell death in our model. We are currently ordering these pathways using epistasis experiments. We also found that both radiation and chemotherapy cause AR in worms with activating mutations of either the EGFR protein or the RAS protein. While C. elegans has been used as a model to order apoptotic signaling pathways, it never before has been applied to understand EGFR-mediated mechanisms protecting somatic cells from death in response to cytotoxic therapy.

Key words: C. elegans, EGFR, Accelerated repopulation, clonogenic cell death

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2005 RRS