Extracellular Matrix: A Treasure Trove in Ovarian Cancer Dissemination and Chemotherapeutic Resistance

Valmiki, Surbhi; Aid, M.; Chaitou, Ali R; Zahid, Maria; Valmiki, Mrinaal; Fawzy, Peter; Khan, Safeera

doi:10.7759/cureus.13864

Cited by 9 publications

(15 citation statements)

References 34 publications

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“…These results agree with the proposed essential role for COL1 in OC metastasis. 45 , 46 , 47 , 48 , 49 , 50 The data also reveal a potential role for LAMA5 selectively in spheroids with implications for BCAM. For comparison, we also analysed the expression of the basal membrane protein collagen IV (COL4), which was not detectable in the tumour compartment of all metastases and spheroids (examples in Figure S13 and Table 2 ).…”

Section: Resultsmentioning

confidence: 74%

“…Moreover, no significant effects of BCAM were observed on the adhesion of OC cells to COL1 (Figure S6E–G ), which may be relevant with respect to its known role in OC cell invasion. 45 , 46 , 47 , 48 , 49 , 50 …”

Section: Resultsmentioning

confidence: 99%

“…However, according to previous studies adhesion of OC cells to collagen rather than laminin drives peritoneal dissemination. [45][46][47][48][49][50] Importantly, BCAM has no detectable effect on adhesion to COL1, suggesting that the observed inhibitory effect of BCAM on the single-cell adhesion to LN-511 is of minor significance in this context. On the other hand, BCAM loosens the structure of spheroids, where LAMA5-integrin β1 interaction is essential to maximise compaction, thereby promoting the dispersion of cancer cell spheroids at target sites, which in turn is likely to contribute to peritoneal metastatic spread.…”

Section: Discussionmentioning

confidence: 96%

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Basal cell adhesion molecule promotes metastasis‐associated processes in ovarian cancer

Sivakumar¹,

Lieber²,

Librizzi³

et al. 2023

Clinical & Translational Med

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Background Basal cell adhesion molecule (BCAM) is a laminin α5 (LAMA5) binding membrane‐bound protein with a putative role in cancer. Besides full‐length BCAM1, an isoform lacking most of the cytoplasmic domain (BCAM2), and a soluble form (sBCAM) of unknown function are known. In ovarian carcinoma (OC), all BCAM forms are abundant and associated with poor survival, yet BCAM's contribution to peritoneal metastatic spread remains enigmatic. Methods Biochemical, omics‐based and real‐time cell assays were employed to identify the source of sBCAM and metastasis‐related functions of different BCAM forms. OC cells, explanted omentum and a mouse model of peritoneal colonisation were used in loss‐ and gain‐of‐function experiments. Results We identified ADAM10 as a major BCAM sheddase produced by OC cells and identified proteolytic cleavage sites proximal to the transmembrane domain. Recombinant soluble BCAM inhibited single‐cell adhesion and migration identically to membrane‐bound isoforms, confirming its biological activity in OC. Intriguingly, this seemingly anti‐tumorigenic potential of BCAM contrasts with a novel pro‐metastatic function discovered in the present study. Thus, all queried BCAM forms decreased the compactness of tumour cell spheroids by inhibiting LAMA5 – integrin β1 interactions, promoted spheroid dispersion in a three‐dimensional collagen matrix, induced clearance of mesothelial cells at spheroid attachment sites in vitro and enhanced invasion of spheroids into omental tissue both ex vivo and in vivo. Conclusions Membrane‐bound BCAM as well as sBCAM shed by ADAM10 act as decoys rather than signalling receptors to modulate metastasis‐related functions. While BCAM appears to have tumour‐suppressive effects on single cells, it promotes the dispersion of OC cell spheroids by regulating LAMA5‐integrin‐β1‐dependent compaction and thereby facilitating invasion of metastatic target sites. As peritoneal dissemination is majorly mediated by spheroids, these findings offer an explanation for the association of BCAM with a poor clinical outcome of OC, suggesting novel therapeutic options.

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Section: Resultsmentioning

confidence: 74%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 96%

See 1 more Smart Citation

Basal cell adhesion molecule promotes metastasis‐associated processes in ovarian cancer

Sivakumar¹,

Lieber²,

Librizzi³

et al. 2023

Clinical & Translational Med

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“…A similar result was seen in GSEA of gene expression data of TCGA ovarian cancer cohort, and we identified that the above-observed gene set of 239 ECM-related genes was positively correlated with a platinum-sensitive phenotype (NES = 3.82, FDR q value <10 −5 ). ECM is a three-dimensional structure composed of glycoproteins, collagens, and proteoglycans and crucial for maintaining cellular homeostasis ( 16 , 17 ), and the ECM has been implicated in the regulation of tumor cell behavioral and response to tumor therapeutics (hormonal and chemotherapeutics) ( 11 , 18 – 20 ). Especially, the tumor-associated matrisome signatures, known as matrix index (MI), could be a predictor for poor prognosis in different kinds of solid tumors ( 19 ).…”

Section: Discussionmentioning

confidence: 99%

High Serpin Family A Member 10 Expression Confers Platinum Sensitivity and Is Associated With Survival Benefit in High-Grade Serous Ovarian Cancer: Based on Quantitative Proteomic Analysis

Guo

et al. 2021

Front. Oncol.

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This study aims to identify differentially expressed proteins related with platinum sensitivity and to find biomarkers for predicting platinum response and survival outcomes in patients with high-grade serous ovarian cancer (HGSOC). Eligible HGSOC patients were divided into platinum-sensitive and platinum-resistant groups according to platinum-free interval (PFI). Tissue protein lysates from tumor tissues were subjected to an in-solution tryptic digest followed by tandem mass tag (TMT) labeling of the resulting peptides and mass spectrometric analysis. Candidate proteins were identified using differentially expressed protein and gene set enrichment analysis (GSEA) and confirmed by immunohistochemistry (IHC), and their survival relevance was evaluated in The Cancer Genome Atlas (TCGA) ovarian cancer cohort. The results showed that there was a significant difference in the protein expression profiling between the two patient groups. In the GSEA model, a gene set of 239 extracellular matrix (ECM)-related proteins was significantly enriched in the platinum-sensitive group [normalized enrichment score (NES) = 3.82, q < 10−5], and this finding was confirmed in TCGA ovarian cancer cohort. Interestingly, an ECM-related gene expression, serpin family A member 10 (SERPINA10), was identified to be significantly positively correlated with overall survival (OS) and progression-free survival (PFS) in TCGA ovarian cancer cohort (all p < 0.05). IHC results demonstrated that HGSOC patients with high SERPINA10 expression had longer PFI than the patients with low SERPINA10 expression (9 vs. 5 months, p = 0.038), and the SERPINA10 expression had an area under the receiver operating characteristic curve (AUC) value of 0.758 (95% CI = 0.612–0.905; p = 0.005) to discriminate the platinum-sensitive group from the platinum-resistant group. In conclusion, the results suggested that SERPINA10 could be a promising biomarker for predicting the response and survival in platinum-based chemotherapy of HGSOC.

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“…First-line conventional treatments for OC are mainly surgery and chemotherapy ( Wang et al, 2016 ; Wang et al, 2019 ). Since many OC patients exhibit primary or secondary resistance to chemotherapeutic agents, new therapeutic approaches need to be discovered to improve the prognosis of OC patients ( Valmiki et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Development and Validation of a Tumor Mutation Burden-Related Immune Prognostic Signature for Ovarian Cancers

et al. 2022

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Ovarian cancer (OC), one of the most common malignancies of the female reproductive system, is characterized by high incidence and poor prognosis. Tumor mutation burden (TMB), as an important biomarker that can represent the degree of tumor mutation, is emerging as a key indicator for predicting the efficacy of tumor immunotherapy. In our study, the gene expression profiles of OC were downloaded from TCGA and GEO databases. Subsequently, we analyzed the prognostic value of TMB in OC and found that a higher TMB score was significantly associated with a better prognosis (p = 0.004). According to the median score of TMB, 9 key TMB related immune prognostic genes were selected by LASSO regression for constructing a TMB associated immune risk score (TMB-IRS) signature, which can effectively predict the prognosis of OC patients (HR = 2.32, 95% CI = 1.68–3.32; AUC = 0.754). Interestingly, TMB-IRS is also closely related to the level of immune cell infiltration and immune checkpoint molecules (PD1, PD-L1, CTLA4, PD-L2) in OC. Furthermore, the nomogram combined with TMB-IRS and a variety of clinicopathological features can more comprehensively evaluate the prognosis of patients. In conclusion, we explored the relationship between TMB and prognosis and validated the TMB-IRS signature based on TMB score in an independent database (HR = 1.60, 95% CI = 1.13–2.27; AUC = 0.639), which may serve as a novel biomarker for predicting OC prognosis as well as possible therapeutic targets.

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Extracellular Matrix: A Treasure Trove in Ovarian Cancer Dissemination and Chemotherapeutic Resistance

Cited by 9 publications

References 34 publications

Basal cell adhesion molecule promotes metastasis‐associated processes in ovarian cancer

Basal cell adhesion molecule promotes metastasis‐associated processes in ovarian cancer

High Serpin Family A Member 10 Expression Confers Platinum Sensitivity and Is Associated With Survival Benefit in High-Grade Serous Ovarian Cancer: Based on Quantitative Proteomic Analysis

Development and Validation of a Tumor Mutation Burden-Related Immune Prognostic Signature for Ovarian Cancers

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