TY - JOUR
T1 - Combinatorial treatment with statins and niclosamide prevents CRC dissemination by unhinging the MACC1-β-catenin-S100A4 axis of metastasis
AU - Kortüm, Benedikt
AU - Radhakrishnan, Harikrishnan
AU - Zincke, Fabian
AU - Sachse, Christoph
AU - Burock, Susen
AU - Keilholz, Ulrich
AU - Dahlmann, Mathias
AU - Walther, Wolfgang
AU - Dittmar, Gunnar
AU - Kobelt, Dennis
AU - Stein, Ulrike
N1 - Funding Information:
We are very grateful to Pia Herrmann, Janice Smith, Margarita Mokritzkij, Markus Hensel and Zeynep Hacer İpek (ECRC, Charité and MDC, Berlin, Germany) for their technical assistance and handling of patient-derived material. We thank Ole Daberkow and Britta Büttner (EPO GmbH, Berlin, Germany) for their assistance in performing the animal experiments, and Anja Arndt for her part in the DigiWest. We are thankful for the human S100A4 promoter to Dr. David Allard, University of Exeter (UK). We also thank the MDC FACS core facility and Dr. H.P. Rahn as well as the FMP for their invaluable technical services. This research was funded by grants from the BIH Innovations & SPARK-BIH Validation Fund, the Berlin School of Integrative Oncology (BSIO) and by the Germany Cancer Consortium (DKTK).
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/9/23
Y1 - 2022/9/23
N2 - Colorectal cancer (CRC) is the second-most common malignant disease worldwide, and metastasis is the main culprit of CRC-related death. Metachronous metastases remain to be an unpredictable, unpreventable, and fatal complication, and tracing the molecular chain of events that lead to metastasis would provide mechanistically linked biomarkers for the maintenance of remission in CRC patients after curative treatment. We hypothesized, that Metastasis-associated in colorectal cancer-1 (MACC1) induces a secretory phenotype to enforce metastasis in a paracrine manner, and found, that the cell-free culture medium of MACC1-expressing CRC cells induces migration. Stable isotope labeling by amino acids in cell culture mass spectrometry (SILAC-MS) of the medium revealed, that S100A4 is significantly enriched in the MACC1-specific secretome. Remarkably, both biomarkers correlate in expression data of independent cohorts as well as within CRC tumor sections. Furthermore, combined elevated transcript levels of the metastasis genes MACC1 and S100A4 in primary tumors and in blood plasma robustly identifies CRC patients at high risk for poor metastasis-free (MFS) and overall survival (OS). Mechanistically, MACC1 strengthens the interaction of β-catenin with TCF4, thus inducing S100A4 synthesis transcriptionally, resulting in elevated secretion to enforce cell motility and metastasis. In cell motility assays, S100A4 was indispensable for MACC1-induced migration, as shown via knock-out and pharmacological inhibition of S100A4. The direct transcriptional and functional relationship of MACC1 and S100A4 was probed by combined targeting with repositioned drugs. In fact, the MACC1-β-catenin-S100A4 axis by statins (MACC1) and niclosamide (S100A4) synergized in inhibiting cancer cell motility in vitro and metastasis in vivo. The MACC1-β-catenin-S100A4 signaling axis is causal for CRC metastasis. Selectively repositioned drugs synergize in restricting MACC1/S100A4-driven metastasis with cross-entity potential.
AB - Colorectal cancer (CRC) is the second-most common malignant disease worldwide, and metastasis is the main culprit of CRC-related death. Metachronous metastases remain to be an unpredictable, unpreventable, and fatal complication, and tracing the molecular chain of events that lead to metastasis would provide mechanistically linked biomarkers for the maintenance of remission in CRC patients after curative treatment. We hypothesized, that Metastasis-associated in colorectal cancer-1 (MACC1) induces a secretory phenotype to enforce metastasis in a paracrine manner, and found, that the cell-free culture medium of MACC1-expressing CRC cells induces migration. Stable isotope labeling by amino acids in cell culture mass spectrometry (SILAC-MS) of the medium revealed, that S100A4 is significantly enriched in the MACC1-specific secretome. Remarkably, both biomarkers correlate in expression data of independent cohorts as well as within CRC tumor sections. Furthermore, combined elevated transcript levels of the metastasis genes MACC1 and S100A4 in primary tumors and in blood plasma robustly identifies CRC patients at high risk for poor metastasis-free (MFS) and overall survival (OS). Mechanistically, MACC1 strengthens the interaction of β-catenin with TCF4, thus inducing S100A4 synthesis transcriptionally, resulting in elevated secretion to enforce cell motility and metastasis. In cell motility assays, S100A4 was indispensable for MACC1-induced migration, as shown via knock-out and pharmacological inhibition of S100A4. The direct transcriptional and functional relationship of MACC1 and S100A4 was probed by combined targeting with repositioned drugs. In fact, the MACC1-β-catenin-S100A4 axis by statins (MACC1) and niclosamide (S100A4) synergized in inhibiting cancer cell motility in vitro and metastasis in vivo. The MACC1-β-catenin-S100A4 signaling axis is causal for CRC metastasis. Selectively repositioned drugs synergize in restricting MACC1/S100A4-driven metastasis with cross-entity potential.
KW - Amino Acids/metabolism
KW - Colonic Neoplasms/genetics
KW - Colorectal Neoplasms/genetics
KW - Gene Expression Regulation, Neoplastic
KW - Humans
KW - Hydroxymethylglutaryl-CoA Reductase Inhibitors
KW - Niclosamide/pharmacology
KW - Rectal Neoplasms/genetics
KW - S100 Calcium-Binding Protein A4/genetics
KW - Trans-Activators/genetics
KW - beta Catenin/metabolism
UR - http://www.scopus.com/inward/record.url?scp=85137037074&partnerID=8YFLogxK
UR - https://pubmed.ncbi.nlm.nih.gov/36008464
U2 - 10.1038/s41388-022-02407-6
DO - 10.1038/s41388-022-02407-6
M3 - Article
C2 - 36008464
AN - SCOPUS:85137037074
SN - 0950-9232
VL - 41
SP - 4446
EP - 4458
JO - Oncogene
JF - Oncogene
IS - 39
ER -