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Breast Cancer Research
Published in: Breast Cancer Research 1/2020

01-12-2020 | Doxycycline | Research article

CRIPTO antagonist ALK4L75A-Fc inhibits breast cancer cell plasticity and adaptation to stress

Authors: Ozlen Balcioglu, Richard E. Heinz, David W. Freeman, Brooke L. Gates, Berhane M. Hagos, Evan Booker, Elnaz Mirzaei Mehrabad, Hyrum T. Diesen, Kishan Bhakta, Supraja Ranganathan, Masami Kachi, Mathias Leblanc, Peter C. Gray, Benjamin T. Spike

Published in: Breast Cancer Research | Issue 1/2020

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Abstract

Background

CRIPTO is a multi-functional signaling protein that promotes stemness and oncogenesis. We previously developed a CRIPTO antagonist, ALK4L75A-Fc, and showed that it causes loss of the stem cell phenotype in normal mammary epithelia suggesting it may similarly inhibit CRIPTO-dependent plasticity in breast cancer cells.

Methods

We focused on two triple negative breast cancer cell lines (MDA-MB-231 and MDA-MB-468) to measure the effects of ALK4L75A-Fc on cancer cell behavior under nutrient deprivation and endoplasmic reticulum stress. We characterized the proliferation and migration of these cells in vitro using time-lapse microscopy and characterized stress-dependent changes in the levels and distribution of CRIPTO signaling mediators and cancer stem cell markers. We also assessed the effects of ALK4L75A-Fc on proliferation, EMT, and stem cell markers in vivo as well as on tumor growth and metastasis using inducible lentiviral delivery or systemic administration of purified ALK4L75A-Fc, which represents a candidate therapeutic approach.

Results

ALK4L75A-Fc inhibited adaptive responses of breast cancer cells under conditions of nutrient and ER stress and reduced their proliferation, migration, clonogenicity, and expression of EMT and cancer stem cell markers. ALK4L75A-Fc also inhibited proliferation of human breast cancer cells in stressed tumor microenvironments in xenografts and reduced both primary tumor size and metastatic burden.

Conclusions

Cancer cell adaptation to stresses such as nutrient deprivation, hypoxia, and chemotherapy can critically contribute to dormancy, metastasis, therapy resistance, and recurrence. Identifying mechanisms that govern cellular adaptation, plasticity, and the emergence of stem-like cancer cells may be key to effective anticancer therapies. Results presented here indicate that targeting CRIPTO with ALK4L75A-Fc may have potential as such a therapy since it inhibits breast cancer cell adaptation to microenvironmental challenges and associated stem-like and EMT phenotypes.
Appendix
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Metadata
Title
CRIPTO antagonist ALK4L75A-Fc inhibits breast cancer cell plasticity and adaptation to stress
Authors
Ozlen Balcioglu
Richard E. Heinz
David W. Freeman
Brooke L. Gates
Berhane M. Hagos
Evan Booker
Elnaz Mirzaei Mehrabad
Hyrum T. Diesen
Kishan Bhakta
Supraja Ranganathan
Masami Kachi
Mathias Leblanc
Peter C. Gray
Benjamin T. Spike
Publication date
01-12-2020
Publisher
BioMed Central
Published in
Breast Cancer Research / Issue 1/2020
Electronic ISSN: 1465-542X
DOI
https://doi.org/10.1186/s13058-020-01361-z

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