Integrative network modeling of colorectal cancer reveals diagnostic signatures and therapeutic targets

Emerging evidence suggests that the interplay between multiple signaling pathways and the immune microenvironment influences tumorigenesis in cancers such as colorectal cancer (CRC). To gain an in-depth understanding of CRC mechanisms and identify novel therapeutic targets, we constructed a molecular interaction map (MIM) integrating key signaling pathways from cancer cells and immune cells within the tumor microenvironment. This map comprises 218 molecules and 328 interactions, curated using PubMed references and official gene symbols. We dynamically simulated the MIM for individual pathways and combinations via stimulus-response and perturbation analyses, calibrating the model with two CRC datasets: GSE1323 (primary tumor-to-metastasis progression) and GSE8671 (normal mucosa-to-adenoma progression), which served as experimental conditions. Simulations revealed distinct disease signatures for GSE1323, including (1) simultaneous activation of TNF/TNFRSF1A,B and EGF/EGFR with inactivation of ERE/ESR, and (2) simultaneous activation of TNF/TNFRSF1A,B and TLR4 with inactivation of ERE/ESR. For GSE8671, the signature was simultaneous activation of TNF/TNFRSF1A,B and TLR4. In silico perturbation analysis identified potent anti-cancer effects from concurrent inhibition of MAPK3 and STAT3 (GSE1323), and ELK1/ATF2 and STAT3 or MAPK14 and STAT3 (GSE8671), significantly reducing epithelial-mesenchymal transition (EMT), proliferation, and inflammation while increasing apoptosis. Disease signatures and therapeutic targets were validated using patient data through Kaplan-Meier survival analysis and machine learning. This integrative model recapitulates cancer biology, predicts biomarkers and therapeutic targets, and is extensible to other immunogenic cancers.