Journal Article

Spontaneous metastasis xenograft models link CD44 isoform 4 to angiogenesis, hypoxia, EMT and mitochondria‐related pathways in colorectal cancer

Nersisyan, Stepan, Stuke, Johanna L., Conradi, Lena‐Christin, Bohnenberger, Hanibal, Tonevitsky, Alexander, Kriegs, Malte, Maar, Hanna, Haider, Marie‐Therese, Schiecke, Alina, Schröder‐Schwarz, Jennifer, Krause, Linda, Itzstein, Mark, Wicklein, Daniel, Everest‐Dass, Arun, Novosad, Victor, Beine, Mia C., Freytag, Vera, Schumacher, Udo, Lange, Tobias, Elakad, Omar, Raygorodskaya, Maria, Maltseva, Diana

2024

Overview

Hematogenous metastasis limits the survival of colorectal cancer (CRC) patients. Here, we illuminated the roles of CD44 isoforms in this process. Isoforms 3 and 4 were predominantly expressed in CRC patients. CD44 isoform 4 indicated poor outcome and correlated with epithelial–mesenchymal transition (EMT) and decreased oxidative phosphorylation (OxPhos) in patients; opposite associations were found for isoform 3. Pan‐CD44 knockdown (kd) independently impaired primary tumor formation and abrogated distant metastasis in CRC xenografts. The xenograft tumors mainly expressed the clinically relevant CD44 isoforms 3 and 4. Both isoforms were enhanced in the paranecrotic, hypoxic tumor regions but were generally absent in lung metastases. Upon CD44 kd, tumor angiogenesis was increased in the paranecrotic areas, accompanied by reduced hypoxia‐inducible factor‐1α and CEACAM5 but increased E‐cadherin expression. Mitochondrial genes and proteins were induced upon pan‐CD44 kd, as were OxPhos genes. Hypoxia increased VEGF release from tumor spheres, particularly upon CD44 kd. Genes affected upon CD44 kd in xenografts specifically overlapped concordantly with genes correlating with CD44 isoform 4 (but not isoform 3) in patients, validating the clinical relevance of the used model and highlighting the metastasis‐promoting role of CD44 isoform 4. Pan‐CD44 knockdown decreases spontaneous metastasis in human colorectal cancer xenograft models. Concurrent intratumoral gene expression alterations significantly correlate with genes differentially regulated among CD44 isoform 4 (but not isoform 3) high vs. low patients (TCGA). The corresponding gene sets and pathways include epithelial–mesenchymal transition, angiogenesis, and OxPhos. CD44 isoform 4 (but not isoform 3) correlates with poor patient outcomes.

• Publisher: John Wiley & Sons, Inc,John Wiley and Sons Inc,Wiley
• Subject: Angiogenesis / Blood vessels / CD44 antigen / CD44 isoforms / Cell Line, Tumor / Colorectal Cancer / Colorectal Neoplasms - pathology / E-cadherin / Endothelium / Epithelial-Mesenchymal Transition - genetics / Ethylenediaminetetraacetic acid / Extracellular matrix / Gene Expression Regulation, Neoplastic / Genes / Genomes / Glycoproteins / Heterografts / HT‐29 / Humans / Hyaluronan Receptors - genetics / Hyaluronan Receptors - metabolism / Hyaluronic acid / Hypoxia / Hypoxia - genetics / Hypoxia-inducible factors / Isoforms / Ligands / Metastases / Metastasis / Motility / Oxidative phosphorylation / Phosphorylation / Protein Isoforms - genetics / Protein Isoforms - metabolism / Proteins / Scientific equipment and supplies industry / Signal transduction / Stem cells / Tumors / Vascular endothelial growth factor / Xenografts