TY - JOUR
T1 - Targeted Therapy to β3 Integrin Reduces Chemoresistance in Breast Cancer Bone Metastases
AU - Fox, Gregory C.
AU - Su, Xinming
AU - Davis, Jennifer L.
AU - Xu, Yalin
AU - Kwakwa, Kristin A.
AU - Ross, Michael H.
AU - Fontana, Francesca
AU - Xiang, Jingyu
AU - Esser, Alison K.
AU - Cordell, Elizabeth
AU - Pagliai, Kristen
AU - Dang, Ha X.
AU - Sivapackiam, Jothilingam
AU - Stewart, Sheila A.
AU - Maher, Christopher A.
AU - Bakewell, Suzanne J.
AU - Fitzpatrick, James A.J.
AU - Sharma, Vijay
AU - Achilefu, Samuel
AU - Veis, Deborah J.
AU - Lanza, Gregory M.
AU - Weilbaecher, Katherine N.
N1 - Funding Information:
This study was supported in whole or in part by the following grants: NCI R01 CA216840 (to G.C. Fox, X. Su, J.L. Davis, Y. Xu, K.A. Kwakwa, M.H. Ross, F. Fontana, J. Xiang, A.K. Esser, G.M. Lanza, K.N. Weilbaecher), NCI P01 CA100730 (to G.C. Fox, X. Su, Y. Xu, M.H. Ross, F. Fontana, J. Xiang, A.K. Esser, K.N. Weilbaecher), NIH U54CA199092 (S. Achilefu, K.N. Weilbaecher), DoD BCRP W81XWH-16-1-0286 (S. Achilefu, X. Su, K.N. Weilbaecher), NIAMS R21 AR073507 (to D.J. Veis), NIAMS R01 AR070030 (to D.J. Veis), NHLBI R01 HL111163 (to J. Sivapackiam, V. Sharma), NHLBI R01 HL142297 (to J. Sivapackiam, V. Sharma), NIBIB P41 EB025815 (to J. Sivapackiam, V. Sharma), and training grants NIAMS T32AR060719 (to G.C. Fox and M.H. Ross) and NIGMS GM07200 (to G.C. Fox). Additional support was provided by the Genome Technology Access Center for sequencing (NIDDK P30-CA91842, ICTS/CTSA UL1TR002345); the Washington University Center for Cellular Imaging (WUCCI) for contributions to preparation, acquisition, and interpretation of electron microscopy data (CDI-CORE-2015–505, CDI-CORE-2019–813, Foundation for Barnes-Jewish Hospital 3770, NCI P30-CA091842, NIH ORIP OD021694); the Musculoskeletal Research Center for histology and radiography (NIAMS P30-AR057235); the Molecular Imaging Center at Washington University for bioluminescence imaging (NCI S10 OD02742, to S. Achilefu); the Alvin J. Siteman Cancer Center Biostatistics Shared Resource for statistical analysis of patient clinical data (NCI P30 CA091842); the Pat Burkhart Breast Cancer Fund, the Barnes-Jewish Foundation, the St. Louis Men’`s Group Against Cancer (to K.Weilbaecher). The authors also acknowledge Vecteezy and BioRender for graphics, and the Hope Center Alafi Neuroimaging Lab (NIH Shared Instrumentation Grant S10 RR027552). The authors thank Drs. Jason Mills, Kareem Azab, David Ornitz, Roberta Faccio, and Vivek Arora for their incisive suggestions and criticism. We gratefully acknowledge Crystal Idleburg, Lynne Collins, Julie Prior, Laura Luecking, Tom Walsh, Dr. Rosy Luo, Dr. Kathryn Tormos, Craig Smith, Dr. Erica Lantelme, Dorjan Brinja, Max Fisher, Dr. Sanja Sviben, Dr. Greg Strout, and Dr. Peter Bayguinov for their invaluable technical assistance and expertise.
Publisher Copyright:
© 2021 American Association for Cancer Research.
PY - 2021/6
Y1 - 2021/6
N2 - Breast cancer bone metastases are common and incurable. Tumoral integrin b3 (b3) expression is induced through interaction with the bone microenvironment. Although b3 is known to promote bone colonization, its functional role during therapy of established bone metastases is not known. We found increased numbers of b3þ tumor cells in murine bone metastases after docetaxel chemotherapy. b3þ tumor cells were present in 97% of post-neoadjuvant chemotherapy triple-negative breast cancer patient samples (n ¼ 38). High tumoral b3 expression was associated with worse outcomes in both pre- and postchemotherapy triple-negative breast cancer groups. Genetic deletion of tumoral b3 had minimal effect in vitro, but significantly enhanced in vivo docetaxel activity, particularly in the bone. Rescue experiments confirmed that this effect required intact b3 signaling. Ultrastructural, transcriptomic, and functional analyses revealed an alternative metabolic response to chemotherapy in b3-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 b3-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 avb3 integrins enhanced docetaxel efficacy in bone metastases. Taken together, we show that b3 integrin induction by the bone microenvironment promotes resistance to chemotherapy through an altered metabolic response that can be defused by combination with avb3-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.
AB - Breast cancer bone metastases are common and incurable. Tumoral integrin b3 (b3) expression is induced through interaction with the bone microenvironment. Although b3 is known to promote bone colonization, its functional role during therapy of established bone metastases is not known. We found increased numbers of b3þ tumor cells in murine bone metastases after docetaxel chemotherapy. b3þ tumor cells were present in 97% of post-neoadjuvant chemotherapy triple-negative breast cancer patient samples (n ¼ 38). High tumoral b3 expression was associated with worse outcomes in both pre- and postchemotherapy triple-negative breast cancer groups. Genetic deletion of tumoral b3 had minimal effect in vitro, but significantly enhanced in vivo docetaxel activity, particularly in the bone. Rescue experiments confirmed that this effect required intact b3 signaling. Ultrastructural, transcriptomic, and functional analyses revealed an alternative metabolic response to chemotherapy in b3-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 b3-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 avb3 integrins enhanced docetaxel efficacy in bone metastases. Taken together, we show that b3 integrin induction by the bone microenvironment promotes resistance to chemotherapy through an altered metabolic response that can be defused by combination with avb3-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.
UR - http://www.scopus.com/inward/record.url?scp=85106995149&partnerID=8YFLogxK
U2 - 10.1158/1535-7163.MCT-20-0931
DO - 10.1158/1535-7163.MCT-20-0931
M3 - Article
C2 - 33785647
AN - SCOPUS:85106995149
SN - 1535-7163
VL - 20
SP - 1183
EP - 1198
JO - Molecular Cancer Therapeutics
JF - Molecular Cancer Therapeutics
IS - 6
ER -