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Role of BCAM in ovarian cancer metastasis
Ovarian cancer (OC) is one of the deadliest gynecological malignancies due to its early and wide-spread peritoneal dissemination, with the omentum being the preferred site of metastasis. The underlying molecular mechanisms are not yet fully understood. Basal cell adhesion molecule (BCAM) is a lam...
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| Format: | Doctoral Thesis |
| Language: | English |
| Published: |
Philipps-Universität Marburg
2023
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| Online Access: | PDF Full Text |
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| Summary: | Ovarian cancer (OC) is one of the deadliest gynecological malignancies due to its early
and wide-spread peritoneal dissemination, with the omentum being the preferred site
of metastasis. The underlying molecular mechanisms are not yet fully understood.
Basal cell adhesion molecule (BCAM) is a laminin α5 (LAMA5) binding protein. BCAM
is expressed in multiple forms in OC, including the full-length protein (BCAM1), a
splicing variant lacking the cytoplasmic domain (BCAM2) and soluble BCAM (sBCAM).
Although BCAM is associated with a poor survival of OC, its contribution to peritoneal
metastasis remains elusive.
In this study, we identified ADAM10 as a major BCAM sheddase produced by OC cells
and determined the proteolytic cleavage sites. All BCAM forms interfered with the
interaction of LAMA5 with integrin β1 to inhibit the adhesion and migration of tumor
cells on a LAMA5-containing matrix, indicating the functionality of both membranebound
and soluble BCAM. It is, however, unlikely that this effect of BCAM on adherent
tumor cells significantly affects peritoneal dissemination of OC cells, as suggested by
several lines of evidence: (i) the known essential function of collagen I (COL1) rather
than laminins in the adhesion of OC cells to peritoneal organs; (ii) our observation that
BCAM had no detectable effect on COL1-dependent OC cell adhesion; and (iii) the
known pivotal role of tumor cell spheroids rather than single cells in metastatic
dissemination.
We discovered, however, that all forms of BCAM negatively regulate the compactness
of LAMA5-rich tumor cell spheroids, thereby promoting their dispersion in a threedimensional
collagen matrix, which in turn facilitates the clearance of mesothelial cells
and promotes their trans-mesothelial invasion into the omentum. Importantly, we also
observed a significant association between BCAM expression and a poor clinical
outcome in OC, highlighting the potential translational relevance of these findings.
In summary, our study provides new mechanistic insights into the role of BCAM in
ovarian cancer progression and highlights its potential as a therapeutic target for
peritoneal metastasis. |
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| DOI: | 10.17192/z2023.0426 |