Scavenging of Labile Heme by Hemopexin Is a Key Checkpoint in Cancer Growth and Metastases
Giacomo Canesin,
Annalisa Di Ruscio,
Mailin Li,
Simone Ummarino,
Andreas Hedblom,
Reeham Choudhury,
Agnieszka Krzyzanowska,
Eva Csizmadia,
Macarena Palominos,
Anna Stiehm,
Alexander Ebralidze,
Shao-Yong Chen,
Mahmoud A. Bassal,
Ping Zhao,
Emanuela Tolosano,
Laurence Hurley,
Anders Bjartell,
Daniel G. Tenen,
Barbara Wegiel
Affiliations
Giacomo Canesin
Department of Surgery, Division of Surgical Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02214, USA
Annalisa Di Ruscio
Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02214, USA; University of Eastern Piedmont, Department of Translational Medicine, Novara, Italy; Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02214, USA; HMS Initiative for RNA Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02214, USA; Corresponding author
Mailin Li
Department of Surgery, Division of Surgical Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02214, USA; University of Eastern Piedmont, Department of Translational Medicine, Novara, Italy
Simone Ummarino
Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02214, USA; University of Eastern Piedmont, Department of Translational Medicine, Novara, Italy
Andreas Hedblom
Department of Surgery, Division of Surgical Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02214, USA
Reeham Choudhury
Department of Surgery, Division of Surgical Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02214, USA
Agnieszka Krzyzanowska
Department of Translational Medicine, Division of Urological Cancers, Lund University, Malmo, Sweden
Eva Csizmadia
Department of Surgery, Division of Surgical Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02214, USA
Macarena Palominos
Department of Translational Medicine, Division of Urological Cancers, Lund University, Malmo, Sweden
Anna Stiehm
Department of Translational Medicine, Division of Urological Cancers, Lund University, Malmo, Sweden
Alexander Ebralidze
Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02214, USA
Shao-Yong Chen
Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02214, USA
Mahmoud A. Bassal
Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02214, USA
Ping Zhao
College of Pharmacy, University of Arizona, Tucson, AZ 85721, USA
Emanuela Tolosano
Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy
Laurence Hurley
College of Pharmacy, University of Arizona, Tucson, AZ 85721, USA
Anders Bjartell
Department of Translational Medicine, Division of Urological Cancers, Lund University, Malmo, Sweden
Daniel G. Tenen
Cancer Science Institute of Singapore, Singapore; Harvard Stem Cell Institute, Harvard Medical School, Cambridge, MA 02138, USA
Barbara Wegiel
Department of Surgery, Division of Surgical Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02214, USA; Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02214, USA; Corresponding author
Summary: Hemopexin (Hx) is a scavenger of labile heme. Herein, we present data defining the role of tumor stroma-expressed Hx in suppressing cancer progression. Labile heme and Hx levels are inversely correlated in the plasma of patients with prostate cancer (PCa). Further, low expression of Hx in PCa biopsies characterizes poorly differentiated tumors and correlates with earlier time to relapse. Significantly, heme promotes tumor growth and metastases in an orthotopic murine model of PCa, with the most aggressive phenotype detected in mice lacking Hx. Mechanistically, labile heme accumulates in the nucleus and modulates specific gene expression via interacting with guanine quadruplex (G4) DNA structures to promote PCa growth. We identify c-MYC as a heme:G4-regulated gene and a major player in heme-driven cancer progression.Collectively, these results reveal that sequestration of labile heme by Hx may block heme-driven tumor growth and metastases, suggesting a potential strategy to prevent and/or arrest cancer dissemination.
