Netrin signaling mediates survival of dormant epithelial ovarian cancer cells
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Curated by eLife
eLife assessment
Perampalam and colleagues provide solid evidence that Netrin signaling drives survival of non-proliferating ovarian cancer cells and their dissemination. These valuable findings were thought to provide unique insights into the molecular underpinnings of ovarian cancer spread and thus to be of significant interest to cancer biologists. However, the incomplete evidence supporting the role of the described Netrin-dependent mechanism in cancer dormancy was found to be a major shortcoming of the study.
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Abstract
Dormancy in cancer is a clinical state in which residual disease remains undetectable for a prolonged duration. At a cellular level, rare cancer cells cease proliferation and survive chemotherapy and disseminate disease. We utilized a suspension culture model of high grade serous ovarian cancer (HGSOC) cell dormancy and devised a novel CRISPR screening approach to identify genetic requirements for cell survival under growth arrested and spheroid culture conditions. In addition, multiple RNA-seq comparisons were used to identify genes whose expression correlates with survival in dormancy. Combined, these approaches discover the Netrin signaling pathway as critical to dormant HGSOC cell survival. We demonstrate that Netrin-1 and -3, UNC5H receptors, DCC and other fibronectin receptors induce low level ERK activation to promote survival in dormant conditions. Furthermore, we determine that Netrin-1 and -3 overexpression is associated with poor prognosis in HGSOC and demonstrate their overexpression elevates cell survival in dormant conditions. Lastly, Netrin-1 or -3 overexpression contributes to greater spread of disease in a xenograft model of abdominal dissemination. This study highlights Netrin signaling as a key mediator HGSOC cancer cell dormancy and metastasis.
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eLife assessment
Perampalam and colleagues provide solid evidence that Netrin signaling drives survival of non-proliferating ovarian cancer cells and their dissemination. These valuable findings were thought to provide unique insights into the molecular underpinnings of ovarian cancer spread and thus to be of significant interest to cancer biologists. However, the incomplete evidence supporting the role of the described Netrin-dependent mechanism in cancer dormancy was found to be a major shortcoming of the study.
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Reviewer #1 (Public Review):
Summary:
Perampalam et al. describe novel methods for genome-wide CRISPR screening to identify and validate genes essential for HGSOC spheroid viability. In this study, they report that Netrin signaling is essential for maintaining disseminated cancer spheroid survival, wherein overexpression of Netrin pathway genes increases tumor burden in a xenograft model of ovarian cancer. They also show that high netrin expression correlates with poor survival outcomes in ovarian cancer patients. The study provides insights into the biology of netrin signaling in DTC cluster survival and warrants development of therapies to block netrin signaling for treating serous ovarian cancer.
Strengths:
- The study identifies Netrin signaling to be important in disseminated cancer spheroid survival
- A Novel GO-CRISPR methodology …Reviewer #1 (Public Review):
Summary:
Perampalam et al. describe novel methods for genome-wide CRISPR screening to identify and validate genes essential for HGSOC spheroid viability. In this study, they report that Netrin signaling is essential for maintaining disseminated cancer spheroid survival, wherein overexpression of Netrin pathway genes increases tumor burden in a xenograft model of ovarian cancer. They also show that high netrin expression correlates with poor survival outcomes in ovarian cancer patients. The study provides insights into the biology of netrin signaling in DTC cluster survival and warrants development of therapies to block netrin signaling for treating serous ovarian cancer.
Strengths:
- The study identifies Netrin signaling to be important in disseminated cancer spheroid survival
- A Novel GO-CRISPR methodology was used to find key genes and pathways essential for disseminated cancer cell survivalWeaknesses:
- The term dormancy is not fully validated and requires additional confirmation to claim the importance of Netrin signaling in "dormant" cancer survival.
- Findings shown in the study largely relate to cancer dissemination and DTS survival rather than cancer dormancy. -
Reviewer #2 (Public Review):
Summary:
In this article, the authors employed modified CRISPR screens ["guide-only (GO)-CRISPR"] in the attempt to identify the genes which may mediate cancer cell dormancy in the high grade serous ovarian cancer (HGSOC) spheroid culture models. Using this approach, they observed that abrogation of several of the components of the netrin (e.g., DCC, UNC5Hs) and MAPK pathways compromise the survival of non-proliferative ovarian cancer cells. This strategy was complemented by the RNAseq approach which revealed that a number of the components of the netrin pathway are upregulated in non-proliferative ovarian cancer cells and that their overexpression is lost upon disruption of DYRK1A kinase that has been previously demonstrated to play a major role in survival of these cells. Perampalam et al. then employed a …
Reviewer #2 (Public Review):
Summary:
In this article, the authors employed modified CRISPR screens ["guide-only (GO)-CRISPR"] in the attempt to identify the genes which may mediate cancer cell dormancy in the high grade serous ovarian cancer (HGSOC) spheroid culture models. Using this approach, they observed that abrogation of several of the components of the netrin (e.g., DCC, UNC5Hs) and MAPK pathways compromise the survival of non-proliferative ovarian cancer cells. This strategy was complemented by the RNAseq approach which revealed that a number of the components of the netrin pathway are upregulated in non-proliferative ovarian cancer cells and that their overexpression is lost upon disruption of DYRK1A kinase that has been previously demonstrated to play a major role in survival of these cells. Perampalam et al. then employed a battery of cell biology approaches to support the model whereby the Netrin signaling governs the MEK-ERK axis to support survival of non-proliferative ovarian cancer cells. Moreover, the authors show that overexpression of Netrins 1 and 3 bolsters dissemination of ovarian cancer cells in the xenograft mouse model, while also providing evidence that high levels of the aforementioned factors are associated with poor prognosis of HGSOC patients.
Strengths:
Overall it was thought that this study is of potentially broad interest inasmuch as it provides previously unappreciated insights into the potential molecular underpinnings of cancer cell dormancy, which has been associated with therapy resistance, disease dissemination, and relapse as well as poor prognosis. Notwithstanding the potential limitations of cellular models in mimicking cancer cell dormancy, it was thought that the authors provided sufficient support for their model that netrin signaling drives survival of non-proliferating ovarian cancer cells and their dissemination. Collectively, it was thought that these findings hold a promise to significantly contribute to the understanding of the molecular mechanisms of cancer cell dormancy and in the long term may provide a molecular basis to address this emerging major issue in the clinical practice.
Weaknesses:
Several issues were observed regarding methodology and data interpretation. The major concerns were related to the reliability of modelling cancer cell dormancy. To this end, it was relatively hard to appreciate how the employed spheroid model allows to distinguish between dormant and e.g., quiescent or even senescent cells. This was in contrast to solid evidence that netrin signaling stimulates abdominal dissemination of ovarian cancer cells in the mouse xenograft and their survival in organoid culture. Moreover, the role of ERK in mediating the effects of netrin signaling in the context of the survival of non-proliferative ovarian cancer cells was found to be somewhat underdeveloped.
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