TY  - JOUR
A1  - Wieland, Annalena
A1  - Strissel, Pamela L.
A1  - Schorle, Hannah
A1  - Bakirci, Ezgi
A1  - Janzen, Dieter
A1  - Beckmann, Matthias W.
A1  - Eckstein, Markus
A1  - Dalton, Paul D.
A1  - Strick, Reiner
T1  - Brain and breast cancer cells with PTEN loss of function reveal enhanced durotaxis and RHOB dependent amoeboid migration utilizing 3D scaffolds and aligned microfiber tracts
JF  - Cancers
N2  - Background: Glioblastoma multiforme (GBM) and metastatic triple-negative breast cancer (TNBC) with PTEN mutations often lead to brain dissemination with poor patient outcome, thus new therapeutic targets are needed. To understand signaling, controlling the dynamics and mechanics of brain tumor cell migration, we implemented GBM and TNBC cell lines and designed 3D aligned microfibers and scaffolds mimicking brain structures. Methods: 3D microfibers and scaffolds were printed using melt electrowriting. GBM and TNBC cell lines with opposing PTEN genotypes were analyzed with RHO-ROCK-PTEN inhibitors and PTEN rescue using live-cell imaging. RNA-sequencing and qPCR of tumor cells in 3D with microfibers were performed, while scanning electron microscopy and confocal microscopy addressed cell morphology. Results: In contrast to the PTEN wildtype, GBM and TNBC cells with PTEN loss of function yielded enhanced durotaxis, topotaxis, adhesion, amoeboid migration on 3D microfibers and significant high RHOB expression. Functional studies concerning RHOB-ROCK-PTEN signaling confirmed the essential role for the above cellular processes. Conclusions: This study demonstrates a significant role of the PTEN genotype and RHOB expression for durotaxis, adhesion and migration dependent on 3D. GBM and TNBC cells with PTEN loss of function have an affinity for stiff brain structures promoting metastasis. 3D microfibers represent an important tool to model brain metastasizing tumor cells, where RHO-inhibitors could play an essential role for improved therapy.
KW  - 3D tumor model
KW  - 3D microfiber
KW  - amoeboid cell migration
KW  - brain cancer
KW  - breast cancer
KW  - PTEN
KW  - RHO
KW  - ROCK
KW  - durotaxis
KW  - topotaxis
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-248443
SN  - 2072-6694
VL  - 13
IS  - 20
ER  - 
TY  - JOUR
A1  - Thibaudeau, Laure
A1  - Taubenberger, Anna V.
A1  - Holzapfel, Boris M.
A1  - Quent, Verena M.
A1  - Fuehrmann, Tobias
A1  - Hesami, Parisa
A1  - Brown, Toby D.
A1  - Dalton, Paul D.
A1  - Power, Carl A.
A1  - Hollier, Brett G.
A1  - Hutmacher, Dietmar W.
T1  - A tissue-engineered humanized xenograft model of human breast cancer metastasis to bone
JF  - Disease Models & Mechanisms
N2  - The skeleton is a preferred homing site for breast cancer metastasis. To date, treatment options for patients with bone metastases are mostly palliative and the disease is still incurable. Indeed, key mechanisms involved in breast cancer osteotropism are still only partially understood due to the lack of suitable animal models to mimic metastasis of human tumor cells to a human bone microenvironment. In the presented study, we investigate the use of a human tissue-engineered bone construct to develop a humanized xenograft model of breast cancer-induced bone metastasis in a murine host. Primary human osteoblastic cell-seeded melt electrospun scaffolds in combination with recombinant human bone morphogenetic protein 7 were implanted subcutaneously in non-obese diabetic/severe combined immunodeficient mice. The tissue-engineered constructs led to the formation of a morphologically intact 'organ' bone incorporating a high amount of mineralized tissue, live osteocytes and bone marrow spaces. The newly formed bone was largely humanized, as indicated by the incorporation of human bone cells and human-derived matrix proteins. After intracardiac injection, the dissemination of luciferase-expressing human breast cancer cell lines to the humanized bone ossicles was detected by bioluminescent imaging. Histological analysis revealed the presence of metastases with clear osteolysis in the newly formed bone. Thus, human tissue-engineered bone constructs can be applied efficiently as a target tissue for human breast cancer cells injected into the blood circulation and replicate the osteolytic phenotype associated with breast cancer-induced bone lesions. In conclusion, we have developed an appropriate model for investigation of species-specific mechanisms of human breast cancer-related bone metastasis in vivo.
KW  - breast cancer
KW  - bone metastasis
KW  - humanized xenograft model
KW  - melt electrospinning
KW  - tissue engineering
KW  - osteotropism
KW  - in vivo
KW  - stem-cell niche
KW  - human prostate-cancer
KW  - morphogenetic protein
KW  - osteoprogenitor cells
KW  - endochondral ossification
KW  - mouse model
KW  - trabecular bone
KW  - calcium phosphate
KW  - skeletal metastases
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-117466
VL  - 7
IS  - 2
ER  -