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

Breast Cancer Research

Supraja Ranganathan¹  Hyrum T. Diesen²  Elnaz Mirzaei Mehrabad²  Kishan Bhakta²  Richard E. Heinz³  Benjamin T. Spike³  Ozlen Balcioglu³  David W. Freeman³  Brooke L. Gates³  Berhane M. Hagos³  Mathias Leblanc⁴  Peter C. Gray⁴  Masami Kachi⁴  Evan Booker⁴ 

[1] Department of Biochemistry, University of Utah;Department of Oncological Sciences, University of Utah;Huntsman Cancer Institute, University of Utah;Peptide Biology Laboratory, Salk Institute for Biological Studies;

关键词: Breast cancer;    Plasticity;    CRIPTO;    Stress adaptation;    Cancer stem cells;   

DOI  :  10.1186/s13058-020-01361-z

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown