Active remodeling of capillary endothelium via cancer cell-derived MMP9 promotes metastatic brain colonization
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Active remodeling of capillary endothelium via cancer cell-derived MMP9 promotes metastatic brain colonization. / Karreman, Matthia A; Bauer, Alexander T; Solecki, Gergely; Berghoff, Anna S; Mayer, Chanté D; Frey, Katharina; Hebach, Nils; Feinauer, Manuel J; Schieber, Nicole L; Tehranian, Cedric; Mercier, Luc; Singhal, Mahak; Venkataramani, Varun; Schubert, Marc C; Hinze, Daniel; Hölzel, Michael; Helfrich, Iris; Schadendorf, Dirk; Schneider, Stefan W; Westphal, Dana; Augustin, Hellmut G; Goetz, Jacky G; Schwab, Yannick; Wick, Wolfgang; Winkler, Frank.
in: CANCER RES, Jahrgang 83, Nr. 8, 14.04.2023, S. 1299-1314.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Active remodeling of capillary endothelium via cancer cell-derived MMP9 promotes metastatic brain colonization
AU - Karreman, Matthia A
AU - Bauer, Alexander T
AU - Solecki, Gergely
AU - Berghoff, Anna S
AU - Mayer, Chanté D
AU - Frey, Katharina
AU - Hebach, Nils
AU - Feinauer, Manuel J
AU - Schieber, Nicole L
AU - Tehranian, Cedric
AU - Mercier, Luc
AU - Singhal, Mahak
AU - Venkataramani, Varun
AU - Schubert, Marc C
AU - Hinze, Daniel
AU - Hölzel, Michael
AU - Helfrich, Iris
AU - Schadendorf, Dirk
AU - Schneider, Stefan W
AU - Westphal, Dana
AU - Augustin, Hellmut G
AU - Goetz, Jacky G
AU - Schwab, Yannick
AU - Wick, Wolfgang
AU - Winkler, Frank
PY - 2023/4/14
Y1 - 2023/4/14
N2 - UNLABELLED: Crossing the blood-brain barrier is a crucial, rate-limiting step of brain metastasis. Understanding of the mechanisms of cancer cell extravasation from brain microcapillaries is limited as the underlying cellular and molecular processes cannot be adequately investigated using in vitro models and endpoint in vivo experiments. Using ultrastructural and functional imaging, we demonstrate that dynamic changes of activated brain microcapillaries promote the mandatory first steps of brain colonization. Successful extravasation of arrested cancer cells occurred when adjacent capillary endothelial cells (EC) entered into a distinct remodeling process. After extravasation, capillary loops were formed, which was characteristic of aggressive metastatic growth. Upon cancer cell arrest in brain microcapillaries, matrix-metalloprotease 9 (MMP9) was expressed. Inhibition of MMP2/9 and genetic perturbation of MMP9 in cancer cells, but not the host, reduced EC projections, extravasation, and brain metastasis outgrowth. These findings establish an active role of ECs in the process of cancer cell extravasation, facilitated by cross-talk between the two cell types. This extends our understanding of how host cells can contribute to brain metastasis formation and how to prevent it.SIGNIFICANCE: Tracking single extravasating cancer cells using multimodal correlative microscopy uncovers a brain seeding mechanism involving endothelial remodeling driven by cancer cell-derived MMP9, which might enable the development of approaches to prevent brain metastasis. See related commentary by McCarty, p. 1167.
AB - UNLABELLED: Crossing the blood-brain barrier is a crucial, rate-limiting step of brain metastasis. Understanding of the mechanisms of cancer cell extravasation from brain microcapillaries is limited as the underlying cellular and molecular processes cannot be adequately investigated using in vitro models and endpoint in vivo experiments. Using ultrastructural and functional imaging, we demonstrate that dynamic changes of activated brain microcapillaries promote the mandatory first steps of brain colonization. Successful extravasation of arrested cancer cells occurred when adjacent capillary endothelial cells (EC) entered into a distinct remodeling process. After extravasation, capillary loops were formed, which was characteristic of aggressive metastatic growth. Upon cancer cell arrest in brain microcapillaries, matrix-metalloprotease 9 (MMP9) was expressed. Inhibition of MMP2/9 and genetic perturbation of MMP9 in cancer cells, but not the host, reduced EC projections, extravasation, and brain metastasis outgrowth. These findings establish an active role of ECs in the process of cancer cell extravasation, facilitated by cross-talk between the two cell types. This extends our understanding of how host cells can contribute to brain metastasis formation and how to prevent it.SIGNIFICANCE: Tracking single extravasating cancer cells using multimodal correlative microscopy uncovers a brain seeding mechanism involving endothelial remodeling driven by cancer cell-derived MMP9, which might enable the development of approaches to prevent brain metastasis. See related commentary by McCarty, p. 1167.
U2 - 10.1158/0008-5472.CAN-22-3964
DO - 10.1158/0008-5472.CAN-22-3964
M3 - SCORING: Journal article
C2 - 36652557
VL - 83
SP - 1299
EP - 1314
JO - CANCER RES
JF - CANCER RES
SN - 0008-5472
IS - 8
ER -