Stromal Hedgehog pathway activation by IHH suppresses lung adenocarcinoma growth and metastasis by limiting reactive oxygen species

Kasiri, Sahba; Chen, Baozhi; Wilson, Alexandra N.; Reczek, Annika; Mazambani, Simbarashe; Gadhvi, Jashkaran; Noel, Evan; Marriam, Ummay; Mino, Barbara; Lü, Wei; Girard, Luc; Solis, Luisa M.; Luby-Phelps, Katherine; Bishop, Justin A.; Kim, Jung-whan; Kim, James

doi:10.1038/s41388-020-1224-5

Cited by 18 publications

(13 citation statements)

References 79 publications

(114 reference statements)

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“…On the other side, overactivated Hh signaling is associated with the development of basal cell carcinoma and medulloblastoma [ 66 , 67 ], but evidence for a tumor-restraining activity of (mostly stromal) Hh signaling has also been provided for pancreatic [ 68 , 69 , 70 ], colon [ 71 ] and pulmonary [ 72 , 73 , 74 ] malignancies. Another example where Hh exerts tumor-suppressive effects is neuroblastoma (NB), the most frequent solid cancer in infants and young children [ 16 , 18 ].…”

Section: Discussionmentioning

confidence: 99%

Activation of Cilia-Independent Hedgehog/GLI1 Signaling as a Novel Concept for Neuroblastoma Therapy

Koeniger

Brichkina

Nee

et al. 2021

Cancers

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Although being rare in absolute numbers, neuroblastoma (NB) represents the most frequent solid tumor in infants and young children. Therapy options and prognosis are comparably good for NB patients except for the high risk stage 4 class. Particularly in adolescent patients with certain genetic alterations, 5-year survival rates can drop below 30%, necessitating the development of novel therapy approaches. The developmentally important Hedgehog (Hh) pathway is involved in neural crest differentiation, the cell type being causal in the etiology of NB. However, and in contrast to its function in some other cancer types, Hedgehog signaling and its transcription factor GLI1 exert tumor-suppressive functions in NB, rendering GLI1 an interesting new candidate for anti-NB therapy. Unfortunately, the therapeutic concept of pharmacological Hh/GLI1 pathway activation is difficult to implement as NB cells have lost primary cilia, essential organelles for Hh perception and activation. In order to bypass this bottleneck, we have identified a GLI1-activating small molecule which stimulates endogenous GLI1 production without the need for upstream Hh pathway elements such as Smoothened or primary cilia. This isoxazole compound potently abrogates NB cell proliferation and might serve as a starting point for the development of a novel class of NB-suppressive molecules.

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Section: Discussionmentioning

confidence: 99%

Activation of Cilia-Independent Hedgehog/GLI1 Signaling as a Novel Concept for Neuroblastoma Therapy

Koeniger

Brichkina

Nee

et al. 2021

Cancers

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“…This type of pathway activation is common in prostate cancer, hepatocellular carcinoma, pancreatic cancer, and non-small cell lung cancer [ 236 , 237 , 238 , 239 , 240 ]. The Shh ligand can also be secreted by tumor cells and can participate in paracrine signaling, activating the Hh/GLI signaling pathway in both tumor and stromal cells, often seen in pancreatic and prostate cancers [ 34 , 235 , 241 , 242 ]. Lastly, tumor stroma can secrete the Shh ligand in a reverse paracrine mechanism, whereby the ligand will activate the Hh/GLI signaling pathway within tumor cells [ 243 ].…”

Section: The Hh/gli Signaling Pathway In Diseasementioning

confidence: 99%

“…Lastly, tumor stroma can secrete the Shh ligand in a reverse paracrine mechanism, whereby the ligand will activate the Hh/GLI signaling pathway within tumor cells [ 243 ]. In some contexts, this paracrine signaling from the stroma can have a role in restraining tumor progression, further complicating the role of Hh/GLI signaling in cancer progression [ 241 , 242 ]. Each mechanism outlined above involves changes in the activity of Hh/GLI pathway constituents, classifying these as canonical mechanisms of pathway activation.…”

Section: The Hh/gli Signaling Pathway In Diseasementioning

confidence: 99%

Hedgehog/GLI Signaling Pathway: Transduction, Regulation, and Implications for Disease

Sigafoos

Paradise

Fernández-Zapico

2021

Cancers

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The Hh/GLI signaling pathway was originally discovered in Drosophila as a major regulator of segment patterning in development. This pathway consists of a series of ligands (Shh, Ihh, and Dhh), transmembrane receptors (Ptch1 and Ptch2), transcription factors (GLI1–3), and signaling regulators (SMO, HHIP, SUFU, PKA, CK1, GSK3b, etc.) that work in concert to repress (Ptch1, Ptch2, SUFU, PKA, CK1, GSK3b) or activate (Shh, Ihh, Dhh, SMO, GLI1–3) the signaling cascade. Not long after the initial discovery, dysregulation of the Hh/GLI signaling pathway was implicated in human disease. Activation of this signaling pathway is observed in many types of cancer, including basal cell carcinoma, medulloblastoma, colorectal, prostate, pancreatic, and many more. Most often, the activation of the Hh/GLI pathway in cancer occurs through a ligand-independent mechanism. However, in benign disease, this activation is mostly ligand-dependent. The upstream signaling component of the receptor complex, SMO, is bypassed, and the GLI family of transcription factors can be activated regardless of ligand binding. Additional mechanisms of pathway activation exist whereby the entirety of the downstream signaling pathway is bypassed, and PTCH1 promotes cell cycle progression and prevents caspase-mediated apoptosis. Throughout this review, we summarize each component of the signaling cascade, non-canonical modes of pathway activation, and the implications in human disease, including cancer.

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“…Florien reported that loss of IHH might increase stromal expression of ErbB family members, thus accelerating the proliferation of colon cancer cells [21]. The research by Sahba et al suggested that stromal HH pathway activated by IHH inhibited growth and metastasis of lung adenocarcinoma cells by restricting reactive oxygen species [22]. These ndings echoed the prognostic protection effect of IHH in UCEC and the stromal or immune-related biological computing background of IHH in UCEC.…”

Section: Discussionmentioning

confidence: 97%

Immune and Stromal Score-Related Gene Signatures For Risk Stratification of Gynaecologic Cancers

Gao¹,

Liang²,

Wei³

et al. 2021

Preprint

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Background: The immune and stromal landscape of gynaecologic cancers is far from elucidated, and there is a lack of systematic prognostic analysis of the immune or stromal parts of the tumour microenvironment (TME) in all types of gynaecologic cancers. We aimed to establish immune and stromal score-based risk signatures for each type of gynaecologic cancer.Methods: In the present study, using the algorithm of “Estimation of stromal and immune cells in malignant tumours using expression data”, we calculated immune and stromal scores for cervical squamous carcinoma (CESC), uteri corpus endometrial cancer (UCEC) and ovarian cancer (OVCA) from the cancer genome atlas (TCGA) to establish immune and stromal score-based risk signatures. Multi-omics analysis combining single nucleotide polymorphism (SNP), tumour mutation burden (TMB) and gene set variation analysis was further performed to investigate the mechanism of immune and stromal score-based risk signatures in gynaecologic cancers. Eventually, the prognostic value of some signature genes was examined in independent microarrays and aberrant expression of IHH in UCECs through immunohistochemistry. Results: According to the results, the prognosis prediction ability of the immune and stromal score-related risk signatures constructed for pan-gynaecological cancers withstood the tests of tROC curves and Kaplan-Meier survival curves, proving to be effective in risk stratification. Three signature genes, including BNC1, CCDC80, and IHH, were verified in independent datasets to have prognostic value in gynaecologic cancers. Conclusions: In summary, the immune and stromal score-related risk signature constructed in this study might be promising prognostic markers for pan-gynaecological cancers.

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Stromal Hedgehog pathway activation by IHH suppresses lung adenocarcinoma growth and metastasis by limiting reactive oxygen species

Cited by 18 publications

References 79 publications

Activation of Cilia-Independent Hedgehog/GLI1 Signaling as a Novel Concept for Neuroblastoma Therapy

Activation of Cilia-Independent Hedgehog/GLI1 Signaling as a Novel Concept for Neuroblastoma Therapy

Hedgehog/GLI Signaling Pathway: Transduction, Regulation, and Implications for Disease

Immune and Stromal Score-Related Gene Signatures For Risk Stratification of Gynaecologic Cancers

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