TRIM49 Deficiency Stabilizes a Galectin-3/EGR1 Transcriptional Complex That Drives Invasiveness of Gastric Adenocarcinoma

Tissue invasion is an initiating step of the cancer metastatic cascade. Unraveling the mechanisms underlying intracellular signaling pathway rewiring that activates downstream transcriptional machinery to drive invasiveness could help identify improved strategies to prevent and treat metastasis. Through an unbiased genome-wide CRISPR screen in a mouse model of gastric adenocarcinoma (GAC), an E3 ubiquitin ligase, tripartite motif-containing protein 49 (TRIM49), was identified as a potent suppressor of cancer invasiveness. In two thirds of GAC, TRIM49 expression was downregulated in invading cancer cells, in which TRIM49 deficiency correlated with deeper tumor infiltration and lymph node metastasis and was indicative of shorter overall patient survival. In multiple orthotopic GAC mouse models, TRIM49-deficient cancer cells were highly infiltrative, leading to multiorgan metastasis. Mechanistically, galectin-3, a putative regulator of cancer invasion, was stabilized in TRIM49-deficient cancer, largely because of the failure to undergo TRIM49-mediated polyubiquitination and proteasomal degradation. Consequently, galectin-3 assembled a complex with EGR1, thereby regulating transcriptional activities of a proinvasive gene module. As the galectin-3/EGR1 complex acted as a key node relaying proinvasive signaling, its disruption using GB1107, an oral galectin-3 inhibitor, suppressed tissue infiltration and metastasis of patient-derived xenografts. Taken together, a proinvasive galectin-3/EGR1 transcriptional complex was exploited by TRIM49-deficient GAC to fuel tissue invasion, representing an Achilles' heel that is potentially targetable to prevent metastasis. SIGNIFICANCE: A proinvasion galectin-3/EGR1 transcriptional complex is a therapeutic vulnerability in the highly invasive TRIM49-deficient gastric adenocarcinoma, which can be disrupted by the oral galectin-3 inhibitor GB1107 to prevent cancer spreading.