Mathematical modeling links Wnt signaling to emergent patterns of metabolism in colon cancer

Abstract

Cell‐intrinsic metabolic reprogramming is a hallmark of cancer that provides anabolic support to cell proliferation. How reprogramming influences tumor heterogeneity or drug sensitivities is not well understood. Here, we report a self‐organizing spatial pattern of glycolysis in xenograft colon tumors where pyruvate dehydrogenase kinase (PDK1), a negative regulator of oxidative phosphorylation, is highly active in clusters of cells arranged in a spotted array. To understand this pattern, we developed a reaction–diffusion model that incorporates Wnt signaling, a pathway known to upregulate PDK1 and Warburg metabolism. Partial interference with Wnt alters the size and intensity of the spotted pattern in tumors and in the model. The model predicts that Wnt inhibition should trigger an increase in proteins that enhance the range of Wnt ligand diffusion. Not only was this prediction validated in xenograft tumors but similar patterns also emerge in radiochemotherapy‐treated colorectal cancer. The model also predicts that inhibitors that target glycolysis or Wnt signaling in combination should synergize and be more effective than each treatment individually. We validated this prediction in 3D colon tumor spheroids.

Hypothesis: Caco‐2 cell rotational 3D mechanogenomic turing patterns have clinical implications to colon crypts

“…Turing models of metabolism in colon cancer link Wnt signalling and gene circuits. We propose that these gene circuits represent potentially promising novel colon cancer targets to model mathematically . A preclinical confocal colonoscopy study demonstrated that a CLDN1‐binding peptide can visualize overexpressed CLDN1 in colonic adenomas in vivo , and actomyosin meshwork measurements have been used to demonstrate morphogenesis.…”

“…We propose that these distinctive colon mucosa patterns support the presence of morphogenetic feedback mechanisms which are hypothesized to regulate the topological architecture of tissues . Integrating our knowledge about gene circuits and tissue topology mathematically may help to guide the development of novel interventions targeting the glucocorticoid/Notch/Wnt pathways . Dynamic 4D Nucleome algorithms may provide a more powerful predictive model of colon cancer with the applications of machine learning methods …”

“…We propose that these gene circuits represent potentially promising novel colon cancer targets to model mathematically. 12,27 A preclinical confocal colonoscopy study demonstrated that a CLDN1binding peptide can visualize overexpressed CLDN1 in colonic adenomas in vivo, and actomyosin meshwork measurements have been used to demonstrate morphogenesis. Therefore, it is feasible to combine these techniques to assess tight junction geometric patterns potentially useful to monitor the transformation of normal to abnormal (e.g.…”

Inhibition of nuclear Wnt signalling: challenges of an elusive target for cancer therapy

“…Recent work has shown that Wnt signalling can also play a direct role in regulating cancer cell metabolism (Lee et al, , ; Pate et al, ; Sherwood et al, ; Sprowl‐Tanio et al, ). For example, Wnt signalling controls cancer cell metabolism via the regulation of pyruvate dehydrogenase kinase 1 and (Pate et al, ; Sprowl‐Tanio et al, ).…”

“…Regulation of both these genes results in cancer cells favouring aerobic glycolysis or Warburg metabolism, which potentiates a unique therapeutic target in Wnt‐high cancers. Additionally, mathematical modelling and in vitro assays show that a combination therapy targeting Wnt signalling and glycolytic activity has a synergistic effect (Lee et al, ). Currently, there are at least a dozen cancer metabolism drugs in clinical trials, some of which are promising – such as those targeting isocitrate dehydrogenase (IDH1) (Agios®), glutaminase inhibitor CB‐839 from Calithera®, and fatty acid synthase inhibitor TVB‐2640 from 3‐V Biosciences® (Garber, ; Mullard, ).…”