An immune-humanized patient-derived xenograft model of estrogen-independent, hormone receptor positive metastatic breast cancer.

Autor: Scherer SD; Department of Oncological Sciences, University of Utah, 2000 Circle of Hope, Salt Lake City, UT, 84112, USA.; Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope, Salt Lake City, UT, 84112, USA., Riggio AI; Department of Oncological Sciences, University of Utah, 2000 Circle of Hope, Salt Lake City, UT, 84112, USA.; Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope, Salt Lake City, UT, 84112, USA., Haroun F; Department of Oncological Sciences, University of Utah, 2000 Circle of Hope, Salt Lake City, UT, 84112, USA.; Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope, Salt Lake City, UT, 84112, USA., DeRose YS; Department of Oncological Sciences, University of Utah, 2000 Circle of Hope, Salt Lake City, UT, 84112, USA.; Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope, Salt Lake City, UT, 84112, USA., Ekiz HA; Department of Oncological Sciences, University of Utah, 2000 Circle of Hope, Salt Lake City, UT, 84112, USA.; Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope, Salt Lake City, UT, 84112, USA., Fujita M; Department of Oncological Sciences, University of Utah, 2000 Circle of Hope, Salt Lake City, UT, 84112, USA.; Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope, Salt Lake City, UT, 84112, USA., Toner J; Department of Oncological Sciences, University of Utah, 2000 Circle of Hope, Salt Lake City, UT, 84112, USA.; Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope, Salt Lake City, UT, 84112, USA., Zhao L; Department of Oncological Sciences, University of Utah, 2000 Circle of Hope, Salt Lake City, UT, 84112, USA.; Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope, Salt Lake City, UT, 84112, USA., Li Z; Department of Pharmacology and Chemical Biology, UPMC Hillman Cancer Center, Magee Women's Research Institute, University of Pittsburgh, 204 Craft Avenue, Pittsburgh, PA, 15213, USA., Oesterreich S; Department of Pharmacology and Chemical Biology, UPMC Hillman Cancer Center, Magee Women's Research Institute, University of Pittsburgh, 204 Craft Avenue, Pittsburgh, PA, 15213, USA., Samatar AA; Zentalis Pharmaceuticals, Inc., 10835 Road to the Cure, Suite 205, San Diego, CA, 92121, USA., Welm AL; Department of Oncological Sciences, University of Utah, 2000 Circle of Hope, Salt Lake City, UT, 84112, USA. alana.welm@hci.utah.edu.; Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope, Salt Lake City, UT, 84112, USA. alana.welm@hci.utah.edu.
Jazyk: angličtina
Zdroj: Breast cancer research : BCR [Breast Cancer Res] 2021 Oct 30; Vol. 23 (1), pp. 100. Date of Electronic Publication: 2021 Oct 30.
DOI: 10.1186/s13058-021-01476-x
Abstrakt: Background: Metastatic breast cancer (MBC) is incurable, with a 5-year survival rate of 28%. In the USA, more than 42,000 patients die from MBC every year. The most common type of breast cancer is estrogen receptor-positive (ER+), and more patients die from ER+ breast cancer than from any other subtype. ER+ tumors can be successfully treated with hormone therapy, but many tumors acquire endocrine resistance, at which point treatment options are limited. There is an urgent need for model systems that better represent human ER+ MBC in vivo, where tumors can metastasize. Patient-derived xenografts (PDX) made from MBC spontaneously metastasize, but the immunodeficient host is a caveat, given the known role of the immune system in tumor progression and response to therapy. Thus, we attempted to develop an immune-humanized PDX model of ER+ MBC.
Methods: NSG-SGM3 mice were immune-humanized with CD34+ hematopoietic stem cells, followed by engraftment of human ER+ endocrine resistant MBC tumor fragments. Strategies for exogenous estrogen supplementation were compared, and immune-humanization in blood, bone marrow, spleen, and tumors was assessed by flow cytometry and tissue immunostaining. Characterization of the new model includes assessment of the human tumor microenvironment performed by immunostaining.
Results: We describe the development of an immune-humanized PDX model of estrogen-independent endocrine resistant ER+ MBC. Importantly, our model harbors a naturally occurring ESR1 mutation, and immune-humanization recapitulates the lymphocyte-excluded and myeloid-rich tumor microenvironment of human ER+ breast tumors.
Conclusion: This model sets the stage for development of other clinically relevant models of human breast cancer and should allow future studies on mechanisms of endocrine resistance and tumor-immune interactions in an immune-humanized in vivo setting.
(© 2021. The Author(s).)
Databáze: MEDLINE
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