Year: 2021
Type: article
Abstract: Breast cancer bone metastases are common and incurable. Tumoral integrin β3 (β3) expression is induced through interaction with the bone microenvironment. Although β3 is known to promote bone colonization, its functional role during therapy of established bone metastases is not known. We found increased numbers of β3+ tumor cells in murine bone metastases after docetaxel chemotherapy. β3+ tumor cells were present in 97% of post-neoadjuvant chemotherapy triple-negative breast cancer patient samples (n = 38). High tumoral β3 expression was associated with worse outcomes in both pre- and postchemotherapy triple-negative breast cancer groups. Genetic deletion of tumoral β3 had minimal effect in vitro, but significantly enhanced in vivo docetaxel activity, particularly in the bone. Rescue experiments confirmed that this effect required intact β3 signaling. Ultrastructural, transcriptomic, and functional analyses revealed an alternative metabolic response to chemotherapy in β3-expressing cells characterized by enhanced oxygen consumption, reactive oxygen species generation, and protein production. We identified mTORC1 as a candidate for therapeutic targeting of this β3-mediated, chemotherapy-induced metabolic response. mTORC1 inhibition in combination with docetaxel synergistically attenuated murine bone metastases. Furthermore, micelle nanoparticle delivery of mTORC1 inhibitor to cells expressing activated αvβ3 integrins enhanced docetaxel efficacy in bone metastases. Taken together, we show that β3 integrin induction by the bone microenvironment promotes resistance to chemotherapy through an altered metabolic response that can be defused by combination with αvβ3-targeted mTORC1 inhibitor nanotherapy. Our work demonstrates the importance of the metastatic microenvironment when designing treatments and presents new, bone-specific strategies for enhancing chemotherapeutic efficacy.
Source: Molecular Cancer Therapeutics
Authors: Gregory C. Fox, Xinming Su, Jennifer L. Davis, Yalin Xu, Kristin A. Kwakwa, Michael H. Ross, Francesca Fontana, Jingyu Xiang, Alison K. Esser, Elizabeth Cordell, Kristen Pagliai, Ha X. Dang, Jothilingam Sivapackiam, Sheila A. Stewart, Christopher A. Maher, Suzanne J. Bakewell, James A.J. Fitzpatrick, Vijay Sharma, Samuel Achilefu, Deborah J. Veis, Gregory M. Lanza, Katherine N. Weilbaecher
Language: English
Subfield: Immunology and Allergy
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
Funders: U.S. Department of Defense, Foundation for Barnes-Jewish Hospital, Institute of Clinical and Translational Sciences, Computational Diagnostics, Alvin J. Siteman Cancer Center, Hope Center for Neurological Disorders, Georgia Clinical and Translational Science Alliance, National Institutes of Health, Center for Cellular Imaging, Washington University, Musculoskeletal Research Center, Washington University in St. Louis, National Heart, Lung, and Blood Institute, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institute of Biomedical Imaging and Bioengineering, National Center for Research Resources, National Center for Advancing Translational Sciences, Office of Research Infrastructure Programs, National Institutes of Health
Awards: G1078697686, G1114310655, G1220868724, G1234843147, G12431752, G1264468082, G1295840733, G1389837536, G1436029295, Center for Multiple Myeloma Nanotherapy, G1674320327, G1699415014, G1877430494, Development and Translation of Generator-Produced PET Tracer for Myocardial Perfusion Imaging, G2339784649, 3D X-RAY PHASE CONTRAST MICROSCOPE FOR SUBMICRON QUANTITATIVE BIOLOGICAL IMAGING, G2775599718, G2824222223, G3015188539, G304139194, G3401557599, G3455473179, G367447669, G432519384, G4350622906, G4429321274, G4500330726, Role of Mitochondrial Dynamics In Bone Homeostasis, G500294632, G5158171709, G5308646581, STIMULATED IMMUNOPHOTOTHERAPY FOR PRIMARY AND METASTATIC BREAST CANCER, G5387316129, G5850682332, G5908279831, G6120206497, G6141331337, G640430542, G6992116998, G718837903, G7196538893, National Research Service Award-Medical Scientist, G8138012746, WHOLE SLIDE IMAGING SYSTEM FOR TRANSLATIONAL NEUROSCIENCE, G8242737674, G9000006824, G9000024264, G9000036323, G9000037442, G9000059615, G9000080599, G9000126234, G9000131957, G9000132732, G9000167305, G9000168629, G9000206903, G9000249116, G9000304810, G9000319192, G9000337860, Cancer Center Support Grant, Tumor Cell Biology Training Program, G964580632
OpenAlex ID: W3149375277