Metastasis is the primary cause of colorectal cancer (CRC) mortality. To date, the molecular mechanisms underpinning it remain elusive. Metastasis is propagated by driver oncogene/suppressor gene mutations (e.g., KRAS, BRAF, and TP53), accompanied by passenger mutations and underlying genomic instability. To understand the biology of cancer, a unifying framework called the hallmarks of cancer (HoCs) which organizes unique disease complexities was developed by Hanahan and Weinberg. Underlying HoCs, genome instability generates mutational diversity that is amplified by inflammation. Recognizing how lynchpin cell-surface protein expression impacts HoCs will accelerate therapeutic development. We therefore queried if decreased expression (↓~43%) of urokinase plasminogen activator receptor (uPAR) negates HoCs driven by KRAS and PIK3CA mutations in a CRC HCT116 cell line background. Comprehensive proteome coverage (whole cell lysis plus 2 membrane enrichment approaches) coupled with pathway analysis demonstrated that decreased uPAR expression negates essential pathways across the HoCs, particularly those associated with invasion/metastasis, resisting cell death and sustaining proliferation. Our data parallels uPAR CHAT (Cancer Hallmarks Analytics Tool) text mining engine results. Decreased uPAR expression also predominantly altered metastasis-related and uPAR-interacting proteins (e.g., EGFR, caveolin, vitronectin and integrin β4). Collectively, this data demonstrates uPAR to be a critical lynchpin that regulates HoC pathways in a classical CRC mutational background and supports the hypothesis that lowering uPAR expression may be a reasonable therapeutic strategy to abrogate metastasis.