A combined computational and functional approach identifies IGF2BP2 as a driver of chemoresistance in a wide array of pre-clinical models of colorectal cancer

Chemoresistance is a major cause of treatment failure in colorectal cancer (CRC) therapy. In this study, the impact of the IGF2BP family of RNA-binding proteins on CRC chemoresistance was investigated using in silico, in vitro, and in vivo approaches. Gene expression data from a well-characterized c...

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Published in:	Molecular cancer Vol. 22; no. 1; p. 89
Main Authors:	Kendzia, Sandra, Franke, Susanne, Kröhler, Tarek, Golob-Schwarzl, Nicole, Schweiger, Caroline, Toeglhofer, Anna M, Skofler, Christina, Uranitsch, Stefan, El-Heliebi, Amin, Fuchs, Julia, Punschart, Andreas, Stiegler, Philipp, Keil, Marlen, Hoffmann, Jens, Henderson, David, Lehrach, Hans, Yaspo, Marie-Laure, Reinhard, Christoph, Schäfer, Reinhold, Keilholz, Ulrich, Regenbrecht, Christian, Schicho, Rudolf, Fickert, Peter, Lax, Sigurd F, Erdmann, Frank, Schulz, Marcel H, Kiemer, Alexandra K, Haybaeck, Johannes, Kessler, Sonja M
Format:	Journal Article
Language:	English
Published:	England BioMed Central Ltd 30-05-2023 BioMed Central BMC
Subjects:	5-Fluorouracil Acidification Antimitotic agents Antineoplastic agents Binding proteins Biomarkers Cancer Cancer therapies Care and treatment Cell culture Cell cycle Cell Line, Tumor Cell Proliferation - genetics Chemoresistance Chemotherapy Colorectal cancer Colorectal carcinoma Colorectal neoplasms Colorectal Neoplasms - drug therapy Colorectal Neoplasms - genetics Colorectal Neoplasms - pathology DNA polymerases Drug resistance Drug Resistance, Neoplasm - genetics Electron transport chain Gefitinib Gene expression Gene Expression Regulation, Neoplastic Glycolysis Health aspects Humans Immunoprecipitation Instrument industry Insulin Insulin-like growth factors Kinases Laboratories Liver cancer Medical prognosis Metabolism Metastases Metastasis Mitochondria Neoplasm Oncology, Experimental Organoids Oxaliplatin Oxaliplatin - pharmacology Oxygen consumption Pathology Patients Physiological aspects Protein binding Risk factors RNA RNA-binding protein RNA-binding proteins RNA-Binding Proteins - genetics RNA-Binding Proteins - metabolism RNA-directed DNA polymerase Scientific equipment and supplies industry Tumors United States United States > US Neoplasm RNA-binding proteins Colorectal neoplasms Drug resistance
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Summary:	Chemoresistance is a major cause of treatment failure in colorectal cancer (CRC) therapy. In this study, the impact of the IGF2BP family of RNA-binding proteins on CRC chemoresistance was investigated using in silico, in vitro, and in vivo approaches. Gene expression data from a well-characterized cohort and publicly available cross-linking immunoprecipitation sequencing (CLIP-Seq) data were collected. Resistance to chemotherapeutics was assessed in patient-derived xenografts (PDXs) and patient-derived organoids (PDOs). Functional studies were performed in 2D and 3D cell culture models, including proliferation, spheroid growth, and mitochondrial respiration analyses. We identified IGF2BP2 as the most abundant IGF2BP in primary and metastastatic CRC, correlating with tumor stage in patient samples and tumor growth in PDXs. IGF2BP2 expression in primary tumor tissue was significantly associated with resistance to selumetinib, gefitinib, and regorafenib in PDOs and to 5-fluorouracil and oxaliplatin in PDX in vivo. IGF2BP2 knockout (KO) HCT116 cells were more susceptible to regorafenib in 2D and to oxaliplatin, selumitinib, and nintedanib in 3D cell culture. Further, a bioinformatic analysis using CLIP data suggested stabilization of target transcripts in primary and metastatic tumors. Measurement of oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) revealed a decreased basal OCR and an increase in glycolytic ATP production rate in IGF2BP2 KO. In addition, real-time reverse transcriptase polymerase chain reaction (qPCR) analysis confirmed decreased expression of genes of the respiratory chain complex I, complex IV, and the outer mitochondrial membrane in IGF2BP2 KO cells. IGF2BP2 correlates with CRC tumor growth in vivo and promotes chemoresistance by altering mitochondrial respiratory chain metabolism. As a druggable target, IGF2BP2 could be used in future CRC therapy to overcome CRC chemoresistance.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1476-4598 1476-4598
DOI:	10.1186/s12943-023-01787-x