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SUMMARY:Intracellular signaling processes and cell decisions using stochas
 tic algorithms - Carlos Lopez (Vanderbilt University)
DTSTART:20160406T100000Z
DTEND:20160406T104500Z
UID:TALK65329@talks.cam.ac.uk
CONTACT:INI IT
DESCRIPTION:Cancer cells within a tumor environment exhibit a complex and 
 adaptive nature whereby genetically and epigenetically distinct subpopulat
 ions compete for resources. The probabilistic nature of gene expression an
 d intracellular molecular interactions confer a significant amount of stoc
 hasticity in cell fate decisions. This cellular heterogeneity is believed 
 to underlie cases of cancer recurrence\, acquired drug resistance\, and so
 -called exceptional responders. From a population dynamics perspective\, c
 lonal heterogeneity and cell-fate stochasticity are distinct sources of no
 ise\, the former arising from genetic mutations and/or epigenetic transiti
 ons\, extrinsic to the fate decision signaling pathways and the latter bei
 ng intrinsic to biochemical reaction networks. Here\, we present our resul
 ts and ongoing work of a kinetic modeling study based on experimental time
  course data for EGFR-addicted non-small cell lung cancer (PC9) cells in b
 oth parental and isolated sublines. When PC9 c ells are treated with erlot
 inib\, an EGFR inhibitor\, a complex array of division and death cell deci
 sions arise within a given population in response to treatment. Although d
 eterministic (ODE) simulations capture the effects of clonal heterogeneity
  and describe the overall trends of experimentally treated tumor cell popu
 lations\, these are not capable of explaining the observed variability of 
 drug response trajectories\, including response magnitude and time to rebo
 und. Our stochastic simulations\, instead\, capture the effects of intrins
 ically noisy cell fate decisions that cause significant variability in cel
 l population trajectories. These findings indicate that stochastic simulat
 ions are necessary to distinguish the contribution of extrinsic (clonal he
 terogeneity) and intrinsic (cell fate decisions) noise to understand the v
 ariability of cancer-cell response treatment. Furthermore\, they suggest t
 hat\, whereas tumors with distinct clon-al structures are expected to beha
 ve differently in response.&nbsp\;
LOCATION:Seminar Room 1\, Newton Institute
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