Hypoxic memory of tumor intrinsic type I interferon suppression promotes breast cancer metastasis

Hypoxia is a common feature of many solid tumors due to aberrant proliferation and angiogenesis and has been associated with tumor progression and metastasis. Most of the well-known hypoxia effects are mediated through hypoxia-inducible factors (HIFs), but the long-lasting effect of hypoxia beyond t...

Full description

Saved in:
Bibliographic Details
Published inbioRxiv
Main Authors Iriondo, Oihana, Mecenas, Desirea, Li, Yilin, Chin, Christopher R, Thomas, Amal, Amzaleg, Yonatan, Ortiz, Veronica, Mackay, Matthew, Dickerson, Amber, Lee, Grace, Harotoonian, Sevana, Benayoun, Bérénice Anath, Smith, Andrew D, Mason, Christopher, Yu, Min
Format Paper
LanguageEnglish
Published Cold Spring Harbor Cold Spring Harbor Laboratory Press 13.05.2022
Subjects
Angiogenesis
Antigen presentation
Breast cancer
Forkhead protein
FOXO1 protein
Histone deacetylase
Hypoxia
Hypoxia-inducible factors
Immune clearance
Immunological memory
Immunotherapy
Interferon
Long term memory
Metastases
Metastasis
Phenotypes
Solid tumors
Tumor cell lines
Tumor cells
Tumorigenesis
Online AccessGet full text

Cover

More Information
Summary:Hypoxia is a common feature of many solid tumors due to aberrant proliferation and angiogenesis and has been associated with tumor progression and metastasis. Most of the well-known hypoxia effects are mediated through hypoxia-inducible factors (HIFs), but the long-lasting effect of hypoxia beyond the immediate HIF regulation remains less understood. Here we show that hypoxia exerts a prolonged effect through HIF-independent mechanisms to promote metastasis. Using breast cancer patient-derived circulating tumor cell (CTC) lines and common breast cancer cell lines, we found that hypoxia downregulates tumor intrinsic type I interferon (IFN) signaling and its downstream antigen presentation (AP) machinery in luminal breast cancer cells. This effect does not depend on the canonical HIFs but is mediated, at least partially, via forkhead box protein O1 (FOXO1). Moreover, hypoxia induced IFN/AP suppression can last longer than the hypoxic exposure, presenting a hypoxic memory phenotype. Hypoxic memory of IFN/AP downregulation is established by specific hypoxic priming, and cells with hypoxic memory have an enhanced ability for tumorigenesis and metastasis. The histone deacetylase inhibitor (HDACi) Entinostat can erase the hypoxic memory and improve the immune clearance of tumor cells when combined with checkpoint immunotherapies in a syngeneic breast cancer mouse model. These results point to a novel mechanism for hypoxia facilitated tumor progression, through a long-lasting memory that provides advantages for CTCs during the metastatic cascade. Competing Interest Statement The authors have declared no competing interest.
DOI:10.1101/2022.05.12.491632