Deciphering the central role of TMOD2 in colorectal cancer progression and metastasis

ABSTRACT: Tropomodulin-2 (TMOD2) was previously identified as upregulated in the nuclear compartment of highly metastatic KM12SM colorectal cancer (CRC) cells. Here, we aimed to investigate its role using multiple CRC cell lines and patient-derived samples through functional proteomics, bioinformatics, and in vitro and in vivo analyses. TMOD2 expression was significantly elevated in highly metastatic CRC cells at both mRNA and protein levels, correlating TMOD2 high protein expression in CRC patients’ samples with advanced disease stages and poorer patient survival. To analyze TMOD2 role in CRC progression and metastasis, stable overexpression and transient depletion of TMOD2 was investigated in CRC isogenic cells with different metastatic properties. TMOD2 stable overexpression enhanced tumorigenic properties, including adhesion, anchorage-independent growth, and migration in CRC cells, whereas transient silencing of TMOD2 resulted in decreased adhesion and invasion capabilities, highlighting a role of TMOD2 in promoting metastasis. In vivo experiments confirmed the role of TMOD2 in enhancing tumor growth and liver metastasis, with TMOD2-overexpressing cells forming larger subcutaneous tumors and inducing poorly metastatic KM12C CRC cells to colonize the liver efficiently. DIA-LFQ proteomics and IP-LC-MS/MS analyses revealed significant dysregulation of proteins involved in cytoskeletal dynamics, secretion, and focal adhesion upon TMOD2 overexpression. Validation studies confirmed the specific involvement of key proteins, including STAG1 and MARCKS, in TMOD2-modulated pathways. Collectively, the results presented here suggest that TMOD2 plays a pivotal role in CRC progression by modulating cytoskeletal dynamics, enhancing cell adhesion, and promoting metastatic behavior, establishing TMOD2 as a potential therapeutic target in CRC.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Epithelial Cell

DISEASE(S): Colon Cancer

SUBMITTER: Ana Montero Calle  

LAB HEAD: Rodrigo Barderas

PROVIDER: PXD057950 | Pride | 2025-09-14

REPOSITORIES: Pride