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Cellular Oncology
Published in: Cellular Oncology 4/2022

Open Access 28-07-2022 | Original Article

Selective targeting BMP2 and 4 in SMAD4 negative esophageal adenocarcinoma inhibits tumor growth and aggressiveness in preclinical models

Authors: Shulin Li, Sanne J. M. Hoefnagel, Matthew Read, Sybren Meijer, Mark I. van Berge Henegouwen, Suzanne S. Gisbertz, Elena Bonora, David S. H. Liu, Wayne A. Phillips, Silvia Calpe, Ana C. P. Correia, Maria D. C. Sancho-Serra, Sandro Mattioli, Kausilia K. Krishnadath, Members of the Esophageal Adenocarcinoma Study Group Europe (EACSGE)

Published in: Cellular Oncology | Issue 4/2022

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Abstract

Purpose

Abnormalities within the Sonic Hedgehog (SHH), Bone Morphogenetic Protein (BMP) and SMAD4 signalling pathways have been associated with the malignant behavior of esophageal adenocarcinoma (EAC). We recently developed two specific llama-derived antibodies (VHHs), C4C4 and C8C8, which target BMP4 and BMP2/4, respectively. Here we aimed to demonstrate the feasibility of the VHHs for the treatment of EAC and to elucidate its underlying mechanism.

Methods

Gene Set Enrichment Analysis (GSEA) was performed on a TCGA dataset, while expression of SHH, BMP2/4 and SMAD4 was validated in a cohort of EAC patients. The effects of the VHHs were tested on the recently established SMAD4(-) ISO76A primary EAC cell line and its counterpart SMAD4(+) ISO76A. In a patient-derived xenograft (PDX) model, the VHHs were evaluated for their ability to selectively target tumor cells and for their effects on tumor growth and survival.

Results

High expression of BMP2/4 was detected in all SMAD4 negative EACs. SHH upregulated BMP2/4 expression and induced p38 MAPK signaling in the SMAD4(-) ISO76A cells. Inhibition of BMP2/4 by VHHs decreased the aggressive and chemo-resistant phenotype of the SMAD4(-) ISO76A but not of the SMAD4(+) ISO76A cells. In the PDX model, in vivo imaging indicated that VHHs effectively targeted tumor cells. Both VHHs significantly inhibited tumor growth and acted synergistically with cisplatin. Furthermore, we found that C8C8 significantly improved survival of the mice.

Conclusions

Our data indicate that increased BMP2/4 expression triggers aggressive non-canonical BMP signaling in SMAD4 negative EAC. Inhibiting BMP2/4 decreases malignant behavior and improves survival. Therefore, VHHs directed against BMP2/4 hold promise for the treatment of SMAD4 negative EAC.
Appendix
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Metadata
Title
Selective targeting BMP2 and 4 in SMAD4 negative esophageal adenocarcinoma inhibits tumor growth and aggressiveness in preclinical models
Authors
Shulin Li
Sanne J. M. Hoefnagel
Matthew Read
Sybren Meijer
Mark I. van Berge Henegouwen
Suzanne S. Gisbertz
Elena Bonora
David S. H. Liu
Wayne A. Phillips
Silvia Calpe
Ana C. P. Correia
Maria D. C. Sancho-Serra
Sandro Mattioli
Kausilia K. Krishnadath
Members of the Esophageal Adenocarcinoma Study Group Europe (EACSGE)
Publication date
28-07-2022
Publisher
Springer Netherlands
Published in
Cellular Oncology / Issue 4/2022
Print ISSN: 2211-3428
Electronic ISSN: 2211-3436
DOI
https://doi.org/10.1007/s13402-022-00689-2

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Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

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Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
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