TY - JOUR
T1 - High endogenous CCL2 expression promotes the aggressive phenotype of human inflammatory breast cancer
AU - Rogic, Anita
AU - Pant, Ila
AU - Grumolato, Luca
AU - Fernandez-Rodriguez, Ruben
AU - Edwards, Andrew
AU - Das, Suvendu
AU - Sun, Aaron
AU - Yao, Shen
AU - Qiao, Rui
AU - Jaffer, Shabnam
AU - Sachidanandam, Ravi
AU - Akturk, Guray
AU - Karlic, Rosa
AU - Skobe, Mihaela
AU - Aaronson, Stuart A.
N1 - Funding Information:
This research was supported by grants to S.A.A. (P01CA80058, R01CA170702 and UO1 OHO11328) and from the Breast Cancer Research Foundation, and to M.S. from the Susan G. Komen and Milburn Foundations (IBC17512321), Eli Lilly, and the Kathryn Crosby Cancer Research Initiative. The authors also wish to acknowledge support from the Tisch Cancer Institute Shared Resource Facilities (NCI Cancer Center Support Grant P30 CA196521-01) including: Jordy Ochando, Flow Cytometry Core; Jose Javier Bravo-Cordero, Microscopy Core; Jiayi Ji, Biostatistics Facility; Sungyee Kim-Schultz, Human Immune Monitoring Center; and Saboor Hekmaty, Dept. of Oncological Sciences NextSeq Sequencing Facility. We thank Drs. Bronek Pytowski and Dolores Hambard-zumyan for critical reading of the manuscript.
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12
Y1 - 2021/12
N2 - Inflammatory Breast Cancer (IBC) is a highly aggressive malignancy with distinct clinical and histopathological features whose molecular basis is unresolved. Here we describe a human IBC cell line, A3250, that recapitulates key IBC features in a mouse xenograft model, including skin erythema, diffuse tumor growth, dermal lymphatic invasion, and extensive metastases. A3250 cells express very high levels of the CCL2 chemokine and induce tumors enriched in macrophages. CCL2 knockdown leads to a striking reduction in macrophage densities, tumor proliferation, skin erythema, and metastasis. These results establish IBC-derived CCL2 as a key factor driving macrophage expansion, and indirectly tumor growth, with transcriptomic analysis demonstrating the activation of multiple inflammatory pathways. Finally, primary human IBCs exhibit macrophage infiltration and an enriched macrophage RNA signature. Thus, this human IBC model provides insight into the distinctive biology of IBC, and highlights potential therapeutic approaches to this deadly disease.
AB - Inflammatory Breast Cancer (IBC) is a highly aggressive malignancy with distinct clinical and histopathological features whose molecular basis is unresolved. Here we describe a human IBC cell line, A3250, that recapitulates key IBC features in a mouse xenograft model, including skin erythema, diffuse tumor growth, dermal lymphatic invasion, and extensive metastases. A3250 cells express very high levels of the CCL2 chemokine and induce tumors enriched in macrophages. CCL2 knockdown leads to a striking reduction in macrophage densities, tumor proliferation, skin erythema, and metastasis. These results establish IBC-derived CCL2 as a key factor driving macrophage expansion, and indirectly tumor growth, with transcriptomic analysis demonstrating the activation of multiple inflammatory pathways. Finally, primary human IBCs exhibit macrophage infiltration and an enriched macrophage RNA signature. Thus, this human IBC model provides insight into the distinctive biology of IBC, and highlights potential therapeutic approaches to this deadly disease.
UR - http://www.scopus.com/inward/record.url?scp=85119856235&partnerID=8YFLogxK
U2 - 10.1038/s41467-021-27108-8
DO - 10.1038/s41467-021-27108-8
M3 - Article
C2 - 34824220
AN - SCOPUS:85119856235
SN - 2041-1723
VL - 12
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 6889
ER -