Spatial Proximity to Fibroblasts Impacts Molecular Features and Therapeutic Sensitivity of Breast Cancer Cells Influencing Clinical Outcomes.
Using a three-dimensional coculture model, we identified significant subtype-specific changes in gene expression, metabolic, and therapeutic sensitivity profiles of breast cancer cells in contact with cancer-associated fibroblasts (CAF). CAF-induced gene expression signatures predicted clinical outcome and immune-related differences in the microenvironment. We found that fibroblasts strongly protect carcinoma cells from lapatinib, attributable to its reduced accumulation in carcinoma cells and an elevated apoptotic threshold. Fibroblasts from normal breast tissues and stromal cultures of brain metastases of breast cancer had similar effects as CAFs. Using synthetic lethality approaches, we identified molecular pathways whose inhibition sensitizes HER2+breast cancer cells to lapatinib both in vitro and in vivo, including JAK2/STAT3 and hyaluronic acid. Neoadjuvant lapatinib therapy in HER2+breast tumors lead to a significant increase of phospho-STAT3+cancer cells and a decrease in the spatial proximity of proliferating (Ki67+) cells to CAFs impacting therapeutic responses. Our studies identify CAF-induced physiologically and clinically relevant changes in cancer cells and offer novel approaches for overcoming microenvironment-mediated therapeutic resistance. Cancer Res; 76(22); 6495-506. ©2016 AACR.
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. Kornelia_polyak@dfci.harvard.edu andriy.marusyk@moffitt.org.|Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.|Department of Medicine, Harvard Medical School, Boston, Massachusetts.
Andriy
A
Marusyk
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.|BBS Program, Harvard Medical School, Boston, Massachusetts.
Doris P
DP
Tabassum
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.|Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.|Department of Medicine, Harvard Medical School, Boston, Massachusetts.
Michalina
M
Janiszewska
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.|Children's Hospital, Boston, Boston, Massachusetts.
Andrew E
AE
Place
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.|Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.|Department of Medicine, Harvard Medical School, Boston, Massachusetts.
Anne
A
Trinh
Department of Biochemistry and Molecular Genetics, University of Colorado, Aurora, Colorado.
Andrii I
AI
Rozhok
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
Saumyadipta
S
Pyne
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.|Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.|Department of Medicine, Harvard Medical School, Boston, Massachusetts.
Jennifer L
JL
Guerriero
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.|Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.|Department of Medicine, Harvard Medical School, Boston, Massachusetts.
Shaokun
S
Shu
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.|Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.|Department of Medicine, Harvard Medical School, Boston, Massachusetts.
Muhammad
M
Ekram
Thomson Reuters Healthcare & Science, Encinitas, California.
Alexander
A
Ishkin
Massachusetts General Hospital, Boston, Massachusetts.|Department of Neurosurgery, Harvard Medical School, Boston, Massachusetts.
Daniel P
DP
Cahill
Thomson Reuters Healthcare & Science, Encinitas, California.
Yuri
Y
Nikolsky
Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York.
Timothy A
TA
Chan
Lester and Sue Smith Breast Center and the Dan L Duncan Comprehensive Cancer Center, Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas.
Mothaffar F
MF
Rimawi
Lester and Sue Smith Breast Center and the Dan L Duncan Comprehensive Cancer Center, Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas.
Susan
S
Hilsenbeck
Lester and Sue Smith Breast Center and the Dan L Duncan Comprehensive Cancer Center, Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas.
Rachel
R
Schiff
Lester and Sue Smith Breast Center and the Dan L Duncan Comprehensive Cancer Center, Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas.
Kent C
KC
Osborne
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.|Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.|Department of Medicine, Harvard Medical School, Boston, Massachusetts.
Antony
A
Letai
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. Kornelia_polyak@dfci.harvard.edu andriy.marusyk@moffitt.org.|Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.|Department of Medicine, Harvard Medical School, Boston, Massachusetts.|BBS Program, Harvard Medical School, Boston, Massachusetts.|Broad Institute, Cambridge, Massachusetts.
Kornelia
K
Polyak
D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D005347:Fibroblasts / Q000378:metabolism*; D020869:Gene Expression Profiling / Q000379:methods*; D006801:Humans; D016896:Treatment Outcome
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