Senescent peritoneal mesothelium creates a niche for ovarian cancer metastases

Mikuła-Pietrasik, Justyna; Uruski, Paweł; Sosińska, Patrycja; Maksin, Konstantin; Piotrowska‐Kempisty, Hanna; Kucińska, Małgorzata; Murias, Marek; Szubert, Sebastian; Woźniak, Aldona; Szpurek, Dariusz; Sajdak, Stefan; Piwocka, Katarzyna; Tykarski, Andrzej; Książek, Krzysztof

doi:10.1038/cddis.2016.417

Cited by 42 publications

(39 citation statements)

References 26 publications

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“…Mechanistically, this was associated with the activity of GRO-1, HGF, and TGF-β1. The observation that senescent HPMCs may initiate senescence in pEOCs is in opposition to our earlier findings, where we demonstrated using both in vitro and in vivo models, that senescent cells promote critical elements of cancer cell expansion, including adhesion [44], proliferation, migration, invasion [7], and angiogenesis [45]. It is noteworthy, however, that the influence of senescent HPMCs was found exclusively in the established, immortal A2780, OVCAR-3 and SKOV-3 cells, which, due to their genetic aberrations, are unable to become senescent.…”

Section: Discussioncontrasting

confidence: 99%

Deciphering the Molecular Mechanism of Spontaneous Senescence in Primary Epithelial Ovarian Cancer Cells

Pakuła

Mały

Uruski

et al. 2020

Cancers

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Spontaneous senescence of cancer cells remains a puzzling and poorly understood phenomenon. Here we comprehensively characterize this process in primary epithelial ovarian cancer cells (pEOCs). Analysis of tumors from ovarian cancer patients showed an abundance of senescent cells in vivo. Further, serially passaged pEOCs become senescent after a few divisions. These senescent cultures display trace proliferation, high expression of senescence biomarkers (SA-β-Gal, γ-H2A.X), growth-arrest in the G1 phase, increased level of cyclins D1, D2, decreased cyclin B1, up-regulated p16, p21, and p53 proteins, eroded telomeres, reduced activity of telomerase, predominantly non-telomeric DNA damage, activated AKT, AP-1, and ERK1/2 signaling, diminished JNK, NF-κB, and STAT3 pathways, increased formation of reactive oxygen species, unchanged activity of antioxidants, increased oxidative damage to DNA and proteins, and dysfunctional mitochondria. Moreover, pEOC senescence is inducible by normal peritoneal mesothelium, fibroblasts, and malignant ascites via the paracrine activity of GRO-1, HGF, and TGF-β1. Collectively, pEOCs undergo spontaneous senescence in a mosaic, telomere-dependent and telomere-independent manner, plausibly in an oxidative stress-dependent mechanism. The process may also be activated by extracellular stimuli. The biological and clinical significance of pEOC senescence remains to be explored.

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Section: Discussioncontrasting

confidence: 99%

Deciphering the Molecular Mechanism of Spontaneous Senescence in Primary Epithelial Ovarian Cancer Cells

Pakuła

Mały

Uruski

et al. 2020

Cancers

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“…This is supported by the observation that metastatic sites are typically devoid of mesothelial cells [27,28]. It has been hypothesized that OC cells attach to the ECM at preexisting lesions of the mesothelial cell layer, which might occur spontaneously and/or could be triggered by changes in cell morphology due to mesothelial cell activation by components of the malignancy-associated peritoneal fluid [29,30], by the induction of mesothelial cell senescence [31], by myosin-dependent mechanical forces exerted by tumor cells [32], or by mesothelial cell killing by FAS ligand [33]. After passing through gaps in the mesothelial cell layer, cells adhere to, and disrupt, the submesothelial basement membrane to invade into the underlying tissue [27].…”

Section: Introductionmentioning

confidence: 94%

Upregulation of mesothelial genes in ovarian carcinoma cells is associated with an unfavorable clinical outcome and the promotion of cancer cell adhesion

et al. 2020

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A hallmark of ovarian high‐grade serous carcinoma (HGSC) is its early and massive peritoneal dissemination via the peritoneal fluid. It is generally believed that tumor cells must breach the mesothelium of peritoneal organs to adhere to the underlying extracellular matrix (ECM) and initiate metastatic growth. However, the molecular mechanisms underlying these processes are only partially understood. Here, we have analyzed 52 matched samples of spheroids and solid tumor masses (suspected primary lesions and metastases) from 10 patients by targeted sequencing of 21 loci previously proposed as targets of HGSC driver mutations. This analysis revealed very similar patterns of genetic alterations in all samples. One exception was FAT3 with a strong enrichment of mutations in metastases compared with presumed primary lesions in two cases. FAT3 is a putative tumor suppressor gene that codes for an atypical cadherin, pointing a potential role in peritoneal dissemination in a subgroup of HGSC patients. By contrast, transcriptome data revealed clear and consistent differences between tumor cell spheroids from ascites and metastatic lesions, which were mirrored by the in vitro adherence of ascites‐derived spheroids. The adhesion‐induced transcriptional alterations in metastases and adherent cells resembled epithelial–mesenchymal transition, but surprisingly also included the upregulation of a specific subset of mesothelial genes, such as calretinin (CALB2) and podoplanin (PDPN). Consistent with this finding, calretinin staining was also observed in subsets of tumor cells in HGSC metastases, particularly at the invasive tumor edges. Intriguingly, a high expression of either CALB2 or PDPN was strongly associated with a poor clinical outcome. siRNA‐mediated CALB2 silencing triggered the detachment of adherent HGSC cells in vitro and inhibited the adhesion of detached HGSC cells to collagen type I. Our data suggest that the acquisition of a mesenchymal–mesothelial phenotype contributes to cancer cell adhesion to the ECM of peritoneal organs and HGSC progression.

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“…Survival rates for such advanced disease are low, and prognosis is especially poor for postmenopausal women who have experienced a decrease in hormones including estrogen and progesterone [35]. The fact that localized, early stage HGSOC has much higher cure rates highlights that novel detection and prevention methods, as well as methods of killing tumor cells prior to extensive dissemination, will have an enormous impact on increasing survival.…”

Section: Discussionmentioning

confidence: 99%

Eliciting OTUD3/RIPK-Dependent Necroptosis to Prevent Epithelial Ovarian Cancer

Johnson

Bales

Bitler

et al. 2020

Preprint

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Background: There is an urgent need for early prevention strategies against high grade serous ovarian carcinoma (HGSOC), the deadliest gynecologic malignancy. Transformed p53-null fallopian tube epithelium (FTE) cells are precursors of HGSOC that may be eliminated by inducing necroptosis, a programmed form of inflammatory cell death. Induction of necroptosis is dependent upon activation of receptor-interacting serine/threonine-protein kinases 1 and 3 (RIPK1/3). TNFα and progesterone (P4) effectively promote necroptosis. In this study, we explore the activation of necroptosis as an approach to inhibit HGSOC progression.Methods: Using gene ontology sets as a reference, we analyzed publicly available datasets of HGSOC to correlate the expression of necroptosis effectors to clinical outcomes. Using in vitro models of HGSOC we evaluated the effect of TNFα, P4, and α-eleostearic acid on necroptosis.In parallel, the necroptosis inhibitor Necrostatin-1 was used to confirm necroptosis-specific cell death.Results: Expression of the P4 receptor (PGR) was sharply reduced in a HGSOC cohort compared to normal, nonmalignant FTE. However, several genes involved in necroptosis signaling were elevated in HGSOC, including TNF and RIPK1. Increased expression of PGR, the necroptosis effectors TNF and RIPK1/3, as well as ovarian tumor domain-containing deubiquitinase 3 (OTUD3) were associated with higher overall survival in 484 HGSOC cases.HGSOC cells activated necroptosis in response to P4, TNFα, and α-eleostearic acid treatment, while P4 or TNFα treatment of HGSOC cells increased TNF, RIPK1, and OTUD3 expression.OTUD3 is a putative tumor suppressor that stabilizes PTEN and is hypothesized to be functionally similar to the necroptosis inducer, OTUD7B. shRNA knockdown of OTUD3 resulted in decreased PTEN protein and RIPK1 protein. Conclusions:We conclude that necroptosis activation may be a viable prevention strategy that leads to the elimination of transformed FTE "founder" cells and prevents HGSOC tumorigenesis.Our data indicate that HGSOC cells activate necroptosis in response to P4, TNFα, and αeleostearic acid, suggesting that established HGSOC cells may also be eliminated by activating necroptosis. # Log2 fold change of HGSOC (n=11) compared to FTE (n=24) * P-value corrected for false-discovery rate by Benjamini-Hochberg method

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Senescent peritoneal mesothelium creates a niche for ovarian cancer metastases

Cited by 42 publications

References 26 publications

Deciphering the Molecular Mechanism of Spontaneous Senescence in Primary Epithelial Ovarian Cancer Cells

Deciphering the Molecular Mechanism of Spontaneous Senescence in Primary Epithelial Ovarian Cancer Cells

Upregulation of mesothelial genes in ovarian carcinoma cells is associated with an unfavorable clinical outcome and the promotion of cancer cell adhesion

Eliciting OTUD3/RIPK-Dependent Necroptosis to Prevent Epithelial Ovarian Cancer

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