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SOSTDC1 promotes invasion and liver metastasis in colorectal cancer via interaction with ALCAM/CD166

Oncogene volume 39, pages 6085–6098 (2020)Cite this article

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Abstract

The mechanistic basis of liver metastasis in colorectal cancer remains poorly understood. We previously reported that the sclerostin domain containing-1 (SOSTDC1) protein is overexpressed in the secretome of metastatic colorectal cancer cells and can inhibit liver homing. Here, we investigated the mechanisms of SOSTDC1 for promoting invasiveness and progression of colorectal cancer liver metastasis. SOSTDC1 inhibition of BMP4 maintains the expression of cancer stem cell traits, including SOX2 and NANOG. Immunoprecipitation and mass spectrometry analyses reveal the association of SOSTDC1 with ALCAM/CD166, which was confirmed by confocal microscopy and competition ELISA. Interaction with ALCAM is mediated by the N-terminal region of SOSTDC1, which contains a sequence similar to the ALCAM-binding motif used by CD6. Knocking down either SOSTDC1 or ALCAM expression, or using blocking antibodies, reduces the invasive activity by inhibiting Src and PI3K/AKT signaling pathways. In addition, ALCAM interacts with the α2ß1 and α1ß1 integrins, providing a possible link to Src activation. Finally, inoculation of SOSTDC1-silenced metastatic cells increases mouse survival by inhibiting liver metastasis. In conclusion, SOSTDC1 promotes invasion and liver metastasis in colorectal cancer, by overcoming BMP4-specific antimetastatic signals and inducing ALCAM-mediated Src and PI3K/AKT activation. These experiments underscore the potential of SOSTDC1 as a therapeutic target in metastatic colorectal cancer.

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Fig. 1: SOSTDC1 is overexpressed in colorectal cancer metastasis.
Fig. 2: SOSTDC1 promotes cell invasion and activation of signaling pathways.
Fig. 3: SOSTDC1 inhibits BMP4 to maintain expression of stem cell transcription factors.
Fig. 4: SOSTDC1 interacts with ALCAM using a CD6-like motif.
Fig. 5: Truncation of SOSTDC1 N-terminus inhibits ALCAM-mediated migration and invasion.
Fig. 6: ALCAM regulates cell invasion and actin polymerization in a coordinated way with SOSTDC1.
Fig. 7: SOSTDC1/ALCAM expression correlates with liver metastasis. A functional model.

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Acknowledgements

We thank Diego Laxalde, Alejandro Diaz, José Ramón Gutiérrez, Marcos Rodriguez, Eva Calviño, and Gema Elvira for their contributions to the paper. This research was supported by grants from the Ministerio de Ciencia e Innovación (BIO2015-66489-R, RTI2018-095055-B100), Foundation Ramón Areces and PRB3 (ISCIII-SGEFI/FEDER-PT17/0019/0008).

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  1. Department of Molecular Biomedicine, Centro de Investigaciones Biológicas, CSIC, Ramiro de Maeztu 9, 28039, Madrid, Spain

    Rubén A. Bartolomé, Laura Pintado-Berninches, Marta Jaén, Vivian de Los Ríos & J. Ignacio Casal

  2. Protein Alternatives S.L., Tres Cantos, Madrid, Spain

    Juan Ignacio Imbaud

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JIC and RAB designed the study, RAB, LP, MJ, VR, and JII carried out the experiments, RAB and JIC analyzed the data, JII provided reagents and protocols and RAB and JIC wrote the paper.

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Correspondence to Rubén A. Bartolomé or J. Ignacio Casal.

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Bartolomé, R.A., Pintado-Berninches, L., Jaén, M. et al. SOSTDC1 promotes invasion and liver metastasis in colorectal cancer via interaction with ALCAM/CD166. Oncogene 39, 6085–6098 (2020). https://doi.org/10.1038/s41388-020-01419-4

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