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TWIST1 mediated transcriptional activation of SPON2 drives colorectal peritoneal metastasis through stromal cell signaling network

ABSTRACT: Colorectal cancer (CRC) peritoneal metastasis (PM) accounts for 25–35% of stage IV cases. CRC PM carries a median overall survival of 16 months with systemic chemotherapy and an almost 0% five-year survival rate. The molecular mechanisms driving CRC PM remain poorly defined. CRC heterogeneity is classified into four Consensus Molecular Subtypes (CMS1-4), with CRC PM predominantly exhibiting the CMS4 signature—characterized by increased stromal/mesenchymal enrichment and cellular plasticity—features linked to frequent disease progression and therapeutic resistance. Here, we investigated the molecular mechanisms driving CRC PM and CMS4 signature. TWIST1 was identified to be significantly upregulated in CRC PM. We established TWIST1-SPON2 as a novel transcriptional axis contributing to CRC PM tumorigenesis, through mediating tumor-stroma interactions. We identified SPP1, secreted by the tumor stroma, as an upstream regulator of the TWIST1-SPON2 cascade via AKT activation in tumor cells in vitro and in vivo. This defined SPP1-TWIST1-SPON2 signaling circuit is pivotal in shaping the tumor microenvironment and promoting CRC PM progression. The findings establish the SPP1-TWIST1-SPON2 axis as potential biomarkers and therapeutic targets in CRC PM.

ORGANISM(S): Homo sapiens

PROVIDER: GSE319741 | GEO | 2026/02/17

REPOSITORIES: GEO

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Project description:The Colorectal Cancer Subtyping Consortium established four Consensus Molecular Subtypes (CMS) in colorectal cancer: CMS1 (microsatellite-instability [MSI], Immune), CMS2 (Canonical, epithelial), CMS3 (Metabolic), and CMS4 (Mesenchymal). However, in the clinical practice only patients with MSI tumors have experienced a change in the management of their disease. Proteomics has experimented significant technical advances with the implementation of data-independent acquisition (DIA) as the gold-standard for the analysis of large cohort of patients, providing a dynamic framework of the disease and direct information about the effectors of the biological processes. The aim of this study is the characterization of the proteome of colon cancer CMS by DIA–based proteomics and expand the utility of CMS in the clinical practice. CMS were assigned and differences in the protein profiles between CMS were defined and evaluated using a Systems Biology approach. One hundred fifty-eight paraffin samples from colon cancer patients with stage II-III disease treated with adjuvant chemotherapy were analyzed. After applying quality criteria, 1,940 identified and quantified proteins were used for the analyses. CMS1 had an overexpression of proteins related to immune system, specifically neutrophils, phagocytosis and antimicrobial response, and a glycolytic profile. CMS3 had an overexpression of proteins related to metabolic pathways, while CMS2 showed an intermediate protein profile between CMS1-3, but with a characteristic profile regarding translation, adhesion, and mitochondria and metabolism biological processes. Two proteomics subtypes within CMS2 with different protein characteristics and prognosis were identified. CMS4 was the most different group with an overexpression of proteins related to angiogenesis, extracellular matrix, focal adhesion, and complement activation. In conclusion, DIA LC-MS/MS proteomics characterization of CRC CMS established new features for each CMS, such as a higher mitochondrial activity in CMS2 or an overexpression of proteins related to phagocytosis in CMS1, but also confirmed previous findings established using transcriptomics such as an overexpression of proteins related to angiogenesis in CMS4. In this CMS4 subtype, several adhesion-related proteins suggested a high metastatic profile and a possible chemoresistance that may explain the worse prognosis of this subtype. CMS1 was characterized as immune and glycolitic-active subtype, being the combination of immunotherapy and glycolytic inhibitors a possible therapeutic strategy. Additionally, two different CMS2 proteomics-based subtypes with different prognosis and possible therapeutic targets were identified. These proccesses could be used as therapeutic targets in the future.

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TWIST1 mediated transcriptional activation of SPON2 drives colorectal peritoneal metastasis through stromal cell signaling network

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