Metastatic Latency and Immune Evasion Through Autocrine Inhibition of WNT

By S. Malladi, Danilo G. Macalinao, Xin Jin, Lan He, Harihar Basnet, Y. Zou, Elisa de Stanchina, J. Massagué. Cell, 2016

721 citations recorded by the source corpus.

Metastasis frequently develops years after the removal of a primary tumor, from a minority of disseminated cancer cells that survived as latent entities through unknown mechanisms. We isolated latency competent cancer (LCC) cells from early-stage human lung and breast carcinoma cell lines and defined the mechanisms that suppress outgrowth, support long-term survival, and maintain tumor-initiating potential in these cells during the latent metastasis stage. LCC cells show stem cell-like characteristics and express Sox2 and Sox9 transcription factors, which are essential for their survival in host organs under immune surveillance and for metastatic outgrowth under permissive conditions. Through expression of the WNT inhibitor DKK1, LCC cells self-impose a slow-cycling state with broad downregulation of ULBP ligands for NK cells and evasion of NK cell-mediated clearance. By expressing a Sox-dependent stem-like state and actively silencing WNT signaling, LCC cells can enter quiescence and evade innate immunity to remain latent for extended periods.

Subfields: Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/c4e3d5e82cf60c54383f51b802afed6d3bf1ba5e

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Molecular Biology

1. Zena Werb
2. R. Weinberg
3. Hans Clevers
4. Y. Fouad
5. C. Aanei
6. M. Egeblad
7. Raghu Kalluri
8. E. Batlle

In Oncology

1. Zena Werb
2. R. Weinberg
3. Y. Fouad
4. C. Aanei
5. D. Pattabiraman
6. Arthur W. Lambert
7. Raghu Kalluri
8. J. Massagué

Citations in the corpus

• Wnt/ b -Catenin Signaling, Disease, and Emerging Therapeutic Modalities (2017, background): “On the other hand, there is substantial evidence that the outgrowth of metastatic lesions and cancer stem cells is promoted by Wnts themselves (Malladi et al., 2016; Nguyen et al., 2009; Yu et al., 2013; Tammela et al., 2017), suggesting that Porcupine targeting drugs could be beneficial.”
• Roles of the immune system in cancer: from tumor initiation to metastatic progression (2018, background): “Ad-ditionally Ad-ditionally, to overcome the attack of NK cells in experimental metastasis, breast and lung cancer cells down-regulate cell surface NK activators, becoming invisible to detection by NK cells (Malladi et al. 2016).”
• Metabolic reprogramming and cancer progression (2020, methodology): “When in vivo selection was used to identify latency-competent cancer cells, these tumors exhibited a quiescent-like state reminiscent of stem and progenitor cells (102).”
• Revisiting the hallmarks of cancer. (2017, positive): “Cancer cells can enter quiescence or a slow-cycling state and remain latent for extended periods of time [195].”
• Unexpected high rate of early tumor recurrence in patients with HCV-related HCC undergoing interferon-free therapy. (2016, background): “As mentioned, one of the most important partners in allowing or preventing metastatic cell survival and growth is immune cancer surveillance [20].”
• Targeting TGF-β signal transduction for fibrosis and cancer therapy (2022, background): “Under this condition, premalignant cells become disseminated cancer cells, can self-impose a slow-cycling state to remain latent for extended periods [108].”
• Neutrophil extracellular traps produced during inflammation awaken dormant cancer cells in mice (2018, background): “NETs drive dormant cancer cells to initiate proliferation, but T cells and natural killer cells may recognize these disseminated cells as they start to proliferate (2, 3, 43).”
• EMERGING BIOLOGICAL PRINCIPLES OF METASTASIS (2017, positive): “…for their ability to persist in a latent state following seeding of distant organ sites succeed in evading clearance by NK cells through the repression of various NK cell-activating ligands, a program that appears to be tightly coupled with entrance into a quiescent state (Malladi et al., 2016).”
• Transforming Grown Factor-β Signaling in Immunity and Cancer (2019, positive): “Therefore, not only is cytostasis a milder form of tumor suppression compared to apoptosis, but cytostasis may ultimately enable disseminated tumor cells to survive for the eventual initiation of metastasis (Malladi et al., 2016).”
• Systems Biology of Cancer Metastasis (2019, background): “Cellular latency can also emerge via the stochastic switch to self-imposed quiescence of a fraction of the cells, for example, by inhibiting WNT pathways, as the proliferative population is eliminated by immune surveillance(Malladi et al., 2016).”