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SUMMARY:Mathematical modeling of heterogeneity in solid tumors: Emergent p
 atterns of metabolism in colon cancer - Professor John Lowengrub
DTSTART:20170921T140000Z
DTEND:20170921T150000Z
UID:TALK82441@talks.cam.ac.uk
CONTACT:June Rix
DESCRIPTION:Many solid tumors exhibit a striking phenotypic diversity that
  helps the tumor survive harsh circumstances such as the limited availabil
 ity of nutrients\, an attacking immune system or chemotherapy treatment. T
 his can arise over time from genetic mutations or more rapidly from non-ge
 netic changes such as self-organization processes\, where signals produced
  by the tumor cells themselves drive the tumor population to bifurcate int
 o multiple cell states. The idea that heterogeneity could help tumors surv
 ive and grow is well accepted\, but actual mechanisms are poorly understoo
 d. In this talk\, we use multiscale mathematical modeling to investigate t
 he emergence and consequences of non-genetic heterogeneity\, focusing on c
 olon cancer as an example. In particular\, we report on a self-organizing 
 pattern of metabolism in xenograft colon tumors where clusters of highly g
 lycolytic cells are arranged in a regular\, spotted array. To explore the 
 basis for this pattern\, we develop Turing-like reaction-diffusion equatio
 ns describing the interactions between different metabolic cell types\, nu
 trients\, and growth factors. A key component of the model is Wnt signalin
 g\, a pathway known to upregulate glycolysis (Warburg metabolism)\, which 
 is highly active in colon cancer.  Diffusive instability analysis and nonl
 inear simulations characterize the dependence of the patterning on the sig
 nalling processes. The model predicts that partial inhibition of Wnt signa
 ling alters the patterning and the expression of factors that increase the
  range of Wnt ligand diffusion. These predictions are validated in xenogra
 ft tumors and are consistent with expression data in primary human colon c
 ancer. The model also predicts that inhibitors that target glycolysis and/
 or Wnt signaling are not so effective as single therapies for cancer as th
 ey are in combination for synergistic reduction of tumor growth. We valida
 ted this prediction in experiments in vitro using 3D colon tumor spheroids
  and a novel microfluidic device containing vascularized colon micro-tumor
 s. 
LOCATION:MR3\,  Centre for Mathematical Sciences\, Wilberforce Road\, Camb
 ridge
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