The histological growth pattern (HGP) at the interface of colorectal adenocarcinoma liver metastases (CRCLM) and liver parenchyma provides important prognostic information. This study aimed to identify transcriptomic signatures underlying the predominant HGPs in CRCLM. We retrospectively evaluated the HGP of 495 CRCLM of 232 patients with metastasectomy at the University Hospital Regensburg between 2003 and 2016. A representative subset of 106 metastases from 53 patients was analyzed for RNA expression at the metastasis–liver interface using the NanoString nCounter® PanCancer Progression Panel. The most common HGPs in the NanoString subcohort were the infiltrative replacement (rHGP, 47.2%) and the non-infiltrative desmoplastic type (dHGP, 46.3%). Unsupervised clustering of CRCLM gene expression profiles identified four gene clusters, two significantly enriched for pure dHGP or pure rHGP. Differential expression analysis between pure dHGP and all other HGPs (i.e., non-pure dHGP) identified 55 significantly differentially expressed genes. Gene set enrichment analysis corroborated previously reported signals (extracellular matrix organization, stromal/endothelial gene sets, and epithelial-mesenchymal transition enrichment in pure dHGP; glucose metabolism in non-pure dHGP) and additionally revealed α6β4 integrin signaling as feature of non-pure dHGP. Patient identity, rather than HGP, was the dominant driver of gene expression variance, though AGR2 was consistently and significantly overexpressed in non-pure dHGP across different analytical strategies. These findings corroborate known transcriptomic differences between HGPs, identify α6β4 integrin signaling as an additional candidate pathway enriched in non-pure dHGP CRCLM, and underscore the substantial contribution of patient-specific factors to gene expression variability in CRCLM outweighing HGP.