Epithelial ovarian cancer (EOC) is a leading cause of cancer-related death in women. Late-stage diagnosis with significant tumor burden, accompanied by recurrence and chemotherapy resistance, ...contributes to this poor prognosis. These morbidities are known to be tied to events associated with epithelial-mesenchymal transition (EMT) in cancer. During EMT, localized tumor cells alter their polarity, cell–cell junctions, cell–matrix interactions, acquire motility and invasiveness and an exaggerated potential for metastatic spread. Key triggers for EMT include the Transforming Growth Factor-β (TGFβ) family of growth factors which are actively produced by a wide array of cell types within a specific tumor and metastatic environment. Although TGFβ can act as either a tumor suppressor or promoter in cancer, TGFβ exhibits its pro-tumorigenic functions at least in part via EMT. TGFβ regulates EMT both at the transcriptional and post-transcriptional levels as outlined here. Despite recent advances in TGFβ based therapeutics, limited progress has been seen for ovarian cancers that are in much need of new therapeutic strategies. Here, we summarize and discuss several recent insights into the underlying signaling mechanisms of the TGFβ isoforms in EMT in the unique metastatic environment of EOCs and the current therapeutic interventions that may be relevant.
Growth factors in tumor environments are regulators of cell survival and metastasis. Here, we reveal the dichotomy between TGF-β superfamily growth factors BMP and TGF-β/activin and their downstream ...SMAD effectors. Gene expression profiling uncovers SOX2 as a key contextual signaling node regulated in an opposing manner by BMP2, -4, and -9 and TGF-β and activin A to impact anchorage-independent cell survival. We find that SOX2 is repressed by BMPs, leading to a reduction in intraperitoneal tumor burden and improved survival of tumor-bearing mice. Repression of SOX2 is driven by SMAD1-dependent histone H3K27me3 recruitment and DNA methylation at SOX2’s promoter. Conversely, TGF-β, which is elevated in patient ascites, and activin A can promote SOX2 expression and anchorage-independent survival by SMAD3-dependent histone H3K4me3 recruitment. Our findings identify SOX2 as a contextual and contrastingly regulated node downstream of TGF-β members controlling anchorage-independent survival and metastasis in ovarian cancers.
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•SOX2 is a key node for anchorage-independent survival in cancer•SOX2 levels are differentially balanced by TGF-β/activin and BMPs in cancer•BMP9 is a robust intraperitoneal metastasis suppressor by lowering SOX2•SOX2 regulation is contextual and at the transcriptional level
Tumor cell survival upon loss of attachment is critical for metastasis. Shonibare et al. identify SOX2 as a contextual node regulated contrastingly by BMPs and TGF-β. Regulation occurs via distinct SMAD1- and SMAD3-dependent histone recruitment and DNA methylation mechanisms influencing anchorage-independent cell survival and intraperitoneal ovarian cancer metastasis.
Ovarian cancer is the second most common and deadliest cancer of the female reproductive system affecting women in the United States and worldwide. The poor survival outcome seen in ovarian cancer is ...attributed to the subtleness of its early-stage symptoms, resulting in a majority of patients at initial diagnosis presenting with an advanced-stage disease with metastasis to other parts of the body. Hence, there is an urgent need to better understand the molecular etiology of metastasis to help develop effective therapeutic options and improve clinical outcomes in ovarian cancer patients. Ovarian cancer, an intra-abdominal cancer, most preferably undergoes metastasis via peritoneal spread which involves cell-matrix detachment and aggregate formation in the peritoneal cavity, a phenomenon referred to as anchorage-independence. Normal cell-matrix detachment triggers a programmed cell death response called anoikis, and thus, ovarian cancer cells acquire anoikis resistance to enable survival under detached conditions for metastasis. The ovarian cancer tumor environment is enriched with cytokines especially members of the transforming growth factor-beta (TGF-β), which act as key regulators of cell survival and anoikis resistance during metastasis. We have found a significant dichotomy between TGF-β superfamily growth factors BMP and TGF-β/activin, and their downstream SMAD effectors in the regulation of anchorage-independent tumor cell survival in ovarian cancer. Gene expression profiling uncovered SOX2 as a central signaling node regulated in an opposing manner by anoikis-promoting BMP2, 4, and 9, and anoikis-suppressing TGF-β and activin A. Our findings implicate the use of a subset of BMPs as a therapeutic strategy in ovarian cancer and demonstrate a critical role of context-specific SOX2 regulation in controlling anchorage-independent survival and metastasis in ovarian cancer.
The ascites ecosystem in ovarian cancer is inhabited by complex cell types and is bathed in an environment rich in cytokines, chemokines, and growth factors that directly and indirectly impact ...metabolism of cancer cells and tumor associated cells. This milieu of malignant ascites, provides a ‘rich’ environment for the disease to thrive, contributing to every aspect of advanced ovarian cancer, a devastating gynecological cancer with a significant gap in targeted therapeutics. In this perspective we focus our discussions on the ‘acellular’ constituents of this liquid malignant tumor microenvironment, and how they influence metabolic pathways. Growth factors, chemokines and cytokines are known modulators of metabolism and have been shown to impact nutrient uptake and metabolic flexibility of tumors, yet few studies have explored how their enrichment in malignant ascites of ovarian cancer patients contributes to the metabolic requirements of ascites-resident cells. We focus here on TGF-βs, VEGF and ILs, which are frequently elevated in ovarian cancer ascites and have all been described to have direct or indirect effects on metabolism, often through gene regulation of metabolic enzymes. We summarize what is known, describe gaps in knowledge, and provide examples from other tumor types to infer potential unexplored roles and mechanisms for ovarian cancer. The distribution and variation in acellular ascites components between patients poses both a challenge and opportunity to further understand how the ascites may contribute to disease heterogeneity. The review also highlights opportunities for studies on ascites-derived factors in regulating the ascites metabolic environment that could act as a unique signature in aiding clinical decisions in the future.
Sex determining region Y-box 2 (Sox2) is a transcription factor essential for maintaining self-renewal and pluripotency of undifferentiated embryonic stem cells. Sox2 is involved in multiple ...processes of cancer cells, however, regulation of Sox2 expression and the consequences of that regulation in cancer remains elusive. Previously, we demonstrated that BMP9/GDF2 is significantly reduced in expression in ovarian cancer (OVCA) cells, methylated in patient tumors and, promoted anoikis resistance in both breast and OVCA cell lines. In an attempt to identify genes downstream of BMP9 that may provide anoikis resistance, transcriptomics was performed leading to the identification of Sox2, a developmental gene, as being significantly down regulated in response to BMP9. I find that Sox2 expression is broadly suppressed by BMP members including BMP2, BMP4 and BMP9 both in a time and dose dependent manner. To identify the specific ALK receptors utilized for Sox2 repression by BMPs, we used inhibitors to the ALK receptors and find specifically that ALK2 and ALK3 are receptors utilized by BMPs for Sox2 regulation. We also examined if Sox2 repression occurs via SMAD activation and find that SMAD1 activation is required for BMP-mediated Sox2 downregulation. This was validated via sh-RNA based approaches. Data from Sox2 promoter reporter assay suggests the involvement of the Sox2 promoter as the regulatory region involved in BMP-mediated downregulation, which was confirmed by expressing Sox2 from a heterologous CMV promoter which failed to be repressed by BMP. Furthermore, we find that de novo protein and RNA synthesis is required for BMP-mediated Sox2 repression as determined using cycloheximide and actinomycin D respectively. My findings indicate that BMP is a mediator of Sox2 downregulation in cancer, occurring via SMAD1-dependent mechanisms.
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