Paracrine Crosstalk between Fibroblasts and ER+ Breast Cancer Cells Creates an IL1β-Enriched Niche that Promotes Tumor Growth
Sumanta Chatterjee,
Vasudeva Bhat,
Alexei Berdnikov,
Jiahui Liu,
Guihua Zhang,
Edward Buchel,
Janice Safneck,
Aaron J. Marshall,
Leigh C. Murphy,
Lynne-Marie Postovit,
Afshin Raouf
Affiliations
Sumanta Chatterjee
Department of Immunology, Faculty of Health Sciences, University of Manitoba, Winnipeg, MB R3E 0T5, Canada; Research Institute of Oncology & Hematology, CancerCareManitoba, Winnipeg, MB R3E 0V9, Canada
Vasudeva Bhat
Department of Immunology, Faculty of Health Sciences, University of Manitoba, Winnipeg, MB R3E 0T5, Canada; Research Institute of Oncology & Hematology, CancerCareManitoba, Winnipeg, MB R3E 0V9, Canada
Alexei Berdnikov
Department of Surgery, Section of Plastic Surgery, Faculty of Health Sciences, University of Manitoba, Winnipeg, MB R3A 1M5, Canada
Jiahui Liu
Department of Oncology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2E1, Canada
Guihua Zhang
Department of Oncology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2E1, Canada
Edward Buchel
Department of Surgery, Section of Plastic Surgery, Faculty of Health Sciences, University of Manitoba, Winnipeg, MB R3A 1M5, Canada
Janice Safneck
Department of Pathology, Faculty of Health Sciences, University of Manitoba, Winnipeg, MB R3E 3P5, Canada
Aaron J. Marshall
Department of Immunology, Faculty of Health Sciences, University of Manitoba, Winnipeg, MB R3E 0T5, Canada
Leigh C. Murphy
Research Institute of Oncology & Hematology, CancerCareManitoba, Winnipeg, MB R3E 0V9, Canada; Department of Biochemistry and Medical Genetics, Faculty of Health Sciences, University of Manitoba, Winnipeg, MB R3E 0J9, Canada
Lynne-Marie Postovit
Department of Oncology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2E1, Canada; Department of Obstetrics and Gynecology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2E1, Canada
Afshin Raouf
Department of Immunology, Faculty of Health Sciences, University of Manitoba, Winnipeg, MB R3E 0T5, Canada; Research Institute of Oncology & Hematology, CancerCareManitoba, Winnipeg, MB R3E 0V9, Canada; Corresponding author
Summary: Breast cancer-induced activated fibroblasts support tumor progression. However, the role of normal fibroblasts in tumor progression remains controversial. In this study, we used modified patient-derived organoid cultures and demonstrate that constitutively secreted cytokines from normal breast fibroblasts initiate a paracrine signaling mechanism with estrogen receptor-positive (ER+) breast cancer cells, which results in the creation of an interleukin (IL)-1β-enriched microenvironment. We found that this paracrine signaling mechanism is shared between normal and activated fibroblasts. Interestingly, we observed that in reconstructed tumor microenvironment containing autologous ER+ breast cancer cells, activated fibroblasts, and immune cells, tamoxifen is more effective in reducing tumor cell proliferation when this paracrine signaling is blocked. Our findings then suggest that ER+ tumor cells could create a growth-promoting environment without activating stromal fibroblasts and that in breast-conserving surgeries, normal fibroblasts could be a significant modulator of tumor recurrence by enhancing the proliferation of residual breast cancer cells in the tumor-adjacent breast tissue. : Molecular Mechanism of Behavior; Functional Aspects of Cell Biology; Cancer Subject Areas: Molecular Mechanism of Behavior, Functional Aspects of Cell Biology, Cancer
