Aberrations in Notch-Hedgehog signalling reveal cancer stem cells harbouring conserved oncogenic properties associated with hypoxia and immunoevasion

Lai, Alvina G.

doi:10.1038/s41416-019-0572-9

Cited by 45 publications

(31 citation statements)

References 71 publications

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“…Genes with GISTIC values of 2 were annotated as deep amplification events, while genes with values of − 2 were annotated as deep (homozygous) deletion events. Shallow amplification and deletion events were annotated for genes with values of + 1 and − 1 respectively (Chang & Lai, 2019a).…”

Section: Methodsmentioning

confidence: 99%

An immunoevasive strategy through clinically-relevant pan-cancer genomic and transcriptomic alterations of JAK-STAT signaling components

Lai

2019

Mol Med

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BackgroundSince its discovery almost three decades ago, the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway has paved the road for understanding inflammatory and immunity processes related to a wide range of human pathologies including cancer. Several studies have demonstrated the importance of JAK-STAT pathway components in regulating tumor initiation and metastatic progression, yet, the extent of how genetic alterations influence patient outcome is far from being understood.MethodsFocusing on 133 genes involved in JAK-STAT signaling, we investigated genomic, transcriptomic and clinical profiles of over 18,000 patients representing 21 diverse cancer types. We identified a core set of 28 putative gain- or loss-of-function JAK-STAT genes that correlated with survival outcomes using Cox proportional hazards regression and Kaplan-Meier analyses. Differential expression analyses between high- and low-expressing patient groups were performed to evaluate the consequences of JAK-STAT misexpression.ResultsWe found that copy number alterations underpinning transcriptional dysregulation of JAK-STAT pathway genes differ within and between cancer types. Integrated analyses uniting genomic and transcriptomic datasets revealed a core set of JAK-STAT pathway genes that correlated with survival outcomes in brain, renal, lung and endometrial cancers. High JAK-STAT scores were associated with increased mortality rates in brain and renal cancers, but not in lung and endometrial cancers where hyperactive JAK-STAT signaling is a positive prognostic factor. Patients with aberrant JAK-STAT signaling demonstrated pan-cancer molecular features associated with misexpression of genes in other oncogenic pathways (Wnt, MAPK, TGF-β, PPAR and VEGF). Brain and renal tumors with hyperactive JAK-STAT signaling had increased regulatory T cell gene (Treg) expression. A combined model uniting JAK-STAT and Tregs allowed further delineation of risk groups where patients with high JAK-STAT and Treg scores consistently performed the worst.ConclusionProviding a pan-cancer perspective of clinically-relevant JAK-STAT alterations, this study could serve as a framework for future research investigating anti-tumor immunity using combination therapy involving JAK-STAT and immune checkpoint inhibitors.

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Section: Methodsmentioning

confidence: 99%

An immunoevasive strategy through clinically-relevant pan-cancer genomic and transcriptomic alterations of JAK-STAT signaling components

Lai

2019

Mol Med

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“…Such cells were again found in niches with generally low, or hypoxic, oxygen content. These cells are also immune-privileged by attracting immunosuppressive T-cells, myeloid-derived suppressor cells, and tumor-associated macrophages [ 91 ]. Altogether, the balance and synergies between these signaling pathways, and many others such as EGFR and BMP, determine the outcome of cell fate instructions by Notch signaling.…”

Section: The Relevance Of Notch Mutations Amplification Pathwaysmentioning

confidence: 99%

Context Matters: NOTCH Signatures and Pathway in Cancer Progression and Metastasis

Misiorek

Przybyszewska-Podstawka

Kałafut

et al. 2021

Cells

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The Notch signaling pathway is a critical player in embryogenesis but also plays various roles in tumorigenesis, with both tumor suppressor and oncogenic activities. Mutations, deletions, amplifications, or over-expression of Notch receptors, ligands, and a growing list of downstream Notch-activated genes have by now been described for most human cancer types. Yet, it often remains unclear what may be the functional impact of these changes for tumor biology, initiation, and progression, for cancer therapy, and for personalized medicine. Emerging data indicate that Notch signaling can also contribute to increased aggressive properties such as invasion, tumor heterogeneity, angiogenesis, or tumor cell dormancy within solid cancer tissues; especially in epithelial cancers, which are in the center of this review. Notch further supports the “stemness” of cancer cells and helps define the stem cell niche for their long-term survival, by integrating the interaction between cancer cells and the cells of the tumor microenvironment (TME). The complexity of Notch crosstalk with other signaling pathways and its roles in cell fate and trans-differentiation processes such as epithelial-to-mesenchymal transition (EMT) point to this pathway as a decisive player that may tip the balance between tumor suppression and promotion, differentiation and invasion. Here we not only review the literature, but also explore genomic databases with a specific focus on Notch signatures, and how they relate to different stages in tumor development. Altered Notch signaling hereby plays a key role for tumor cell survival and coping with a broad spectrum of vital issues, contributing to failed therapies, poor patient outcome, and loss of lives.

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“…One option is the use of immune checkpoint inhibitors (ICIs), to which, despite showing good results in some cancer types [226,227], most patients still do not respond, likely due to tumor-intrinsic mechanisms of resistance [228]. Interestingly, potential mechanisms may be related to aberrant WNT, Notch, SHH, or STAT3 pathways, which have important roles in GSC maintenance [229][230][231]. This raises the question of whether GSCs, through the upregulation of these developmental pathways, contribute to immune evasion.…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

Exploiting the Complexities of Glioblastoma Stem Cells: Insights for Cancer Initiation and Therapeutic Targeting

Castro

Gonçalves

Hormigo

et al. 2020

IJMS

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The discovery of glioblastoma stem cells (GSCs) in the 2000s revolutionized the cancer research field, raising new questions regarding the putative cell(s) of origin of this tumor type, and partly explaining the highly heterogeneous nature of glioblastoma (GBM). Increasing evidence has suggested that GSCs play critical roles in tumor initiation, progression, and resistance to conventional therapies. The remarkable oncogenic features of GSCs have generated significant interest in better defining and characterizing these cells and determining novel pathways driving GBM that could constitute attractive key therapeutic targets. While exciting breakthroughs have been achieved in the field, the characterization of GSCs is a challenge and the cell of origin of GBM remains controversial. For example, the use of several cell-surface molecular markers to identify and isolate GSCs has been a challenge. It is now widely accepted that none of these markers is, per se, sufficiently robust to distinguish GSCs from normal stem cells. Finding new strategies that are able to more efficiently and specifically target these niches could also prove invaluable against this devastating and therapy-insensitive tumor. In this review paper, we summarize the most relevant findings and discuss emerging concepts and open questions in the field of GSCs, some of which are, to some extent, pertinent to other cancer stem cells.

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Aberrations in Notch-Hedgehog signalling reveal cancer stem cells harbouring conserved oncogenic properties associated with hypoxia and immunoevasion

Cited by 45 publications

References 71 publications

An immunoevasive strategy through clinically-relevant pan-cancer genomic and transcriptomic alterations of JAK-STAT signaling components

An immunoevasive strategy through clinically-relevant pan-cancer genomic and transcriptomic alterations of JAK-STAT signaling components

Context Matters: NOTCH Signatures and Pathway in Cancer Progression and Metastasis

Exploiting the Complexities of Glioblastoma Stem Cells: Insights for Cancer Initiation and Therapeutic Targeting

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