Replication stress and defective checkpoints make fallopian tube epithelial cells putative drivers of high-grade serous ovarian cancer

Pamoda Galhenage; Yunlan Zhou; Erica Perry; Brenda Loc; Kelly Fietz; Sonia Iyer; Ferenc Reinhardt; Tiego Da Silva; Vladimir Botchkarev; Jie Chen; Christopher P. Crum; Robert A. Weinberg; Shailja Pathania

Cell Reports (Oct 2023)

Replication stress and defective checkpoints make fallopian tube epithelial cells putative drivers of high-grade serous ovarian cancer

Pamoda Galhenage,
Yunlan Zhou,
Erica Perry,
Brenda Loc,
Kelly Fietz,
Sonia Iyer,
Ferenc Reinhardt,
Tiego Da Silva,
Vladimir Botchkarev,
Jie Chen,
Christopher P. Crum,
Robert A. Weinberg,
Shailja Pathania

Affiliations

Pamoda Galhenage: Center for Personalized Cancer Therapy, Department of Biology, University of Massachusetts Boston, Boston, MA 02125, USA
Yunlan Zhou: Dana-Farber Cancer Institute, Boston, MA 02215, USA
Erica Perry: Center for Personalized Cancer Therapy, Department of Biology, University of Massachusetts Boston, Boston, MA 02125, USA
Brenda Loc: Center for Personalized Cancer Therapy, Department of Biology, University of Massachusetts Boston, Boston, MA 02125, USA
Kelly Fietz: Center for Personalized Cancer Therapy, Department of Biology, University of Massachusetts Boston, Boston, MA 02125, USA
Sonia Iyer: Whitehead Institute for Biomedical Research, 455 Main Street, WHTH-367, Cambridge, MA 02142, USA
Ferenc Reinhardt: Whitehead Institute for Biomedical Research, 455 Main Street, WHTH-367, Cambridge, MA 02142, USA
Tiego Da Silva: Center for Personalized Cancer Therapy, Department of Biology, University of Massachusetts Boston, Boston, MA 02125, USA
Vladimir Botchkarev: Dana-Farber Cancer Institute, Boston, MA 02215, USA
Jie Chen: Department of Mathematics, University of Massachusetts Boston, Boston, MA 02125, USA
Christopher P. Crum: Department of Pathology, Division of Women’s and Perinatal Pathology, Brigham and Women’s Hospital, Boston, MA 02115, USA
Robert A. Weinberg: Whitehead Institute for Biomedical Research, 455 Main Street, WHTH-367, Cambridge, MA 02142, USA
Shailja Pathania: Center for Personalized Cancer Therapy, Department of Biology, University of Massachusetts Boston, Boston, MA 02125, USA; Corresponding author

Journal volume & issue: Vol. 42, no. 10
p. 113144

Abstract

Read online

Summary: Clinical and molecular evidence indicates that high-grade serous ovarian cancer (HGSOC) primarily originates from the fallopian tube, not the ovarian surface. However, the reasons for this preference remain unclear. Our study highlights significant differences between fallopian tube epithelial (FTE) and ovarian surface epithelial (OSE) cells, providing the molecular basis for FTEs as site of origin of HGSOC. FTEs, unlike OSEs, exhibit heightened replication stress (RS), impaired repair of stalled forks, ineffective G2/M checkpoint, and increased tumorigenicity. BRCA1 heterozygosity exacerbates these defects, resulting in RS suppression haploinsufficiency and an aggressive tumor phenotype. Examination of human and mouse sections reveals buildup of the RS marker 53BP1 primarily in the fallopian tubes, particularly at the fimbrial ends. Furthermore, menopausal status influences RS levels. Our study provides a mechanistic rationale for FTE as the site of origin for HGSOC, investigates the impact of BRCA1 heterozygosity, and lays the groundwork for targeting early HGSOC drivers.

CP: Cancer

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

About the journal

Abstract

Keywords