Mesenchymal Cells Support the Oncogenicity and Therapeutic Response of the Hedgehog Pathway in Triple-Negative Breast Cancer

Reyes-Ramos, Ana M; Ramos-Cruz, Karla P.; Rodríguez-Merced, Nelson J.; Martínez-Montemayor, Michelle M.; Franqui-Ríos, Nelson D; Ríos-Grant, Jan P; Flores, Andrea; Maldonado-Martínez, Gerónimo; Torres-García, Wandaliz; Domenech, Maribella

doi:10.3390/cancers11101522

Cited by 9 publications

(8 citation statements)

References 56 publications

(74 reference statements)

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“…Hh signaling also induces several EMT and invasiveness regulators including Snail family zinc finger 1 (SNAI1), Neuropilin 2 (NRP2), Cysteine-rich angiogenic inducer 61 (CYR61), Matrix metallopeptidase (MMP), and C-X-C chemokine receptor type 4 (CXCR4) [ 66 ] . As with Notch signaling, tumor-stroma interactions have been shown to sustain Hh signaling in TNBC promoting stemness [ 71 ] .…”

Section: Cellular Pathways Regulating Stemness In Tnbcmentioning

confidence: 99%

Regulation of cancer stem cells in triple negative breast cancer

Fultang¹,

Chakraborty²,

Peethambaran³

2021

CDR

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Triple Negative Breast Cancer (TNBC) is the most lethal subtype of breast cancer. Despite the successes of emerging targeted therapies, relapse, recurrence, and therapy failure rates in TNBC significantly outpace other subtypes of breast cancer. Mounting evidence suggests accumulation of therapy resistant Cancer Stem Cell (CSC) populations within TNBCs contributes to poor clinical outcomes. These CSCs are enriched in TNBC compared to non-TNBC breast cancers. The mechanisms underlying CSC accumulation have been well-characterized and discussed in other reviews. In this review, we focus on TNBC-specific mechanisms that allow the expansion and activity of self-renewing CSCs. We highlight cellular signaling pathways and transcription factors, specifically enriched in TNBC over non-TNBC breast cancer, contributing to stemness. We also analyze publicly available singlecell RNA-seq data from basal breast cancer tumors to highlight the potential of emerging bioinformatic approaches in identifying novel drivers of stemness in TNBC and other cancers.

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Section: Cellular Pathways Regulating Stemness In Tnbcmentioning

confidence: 99%

Regulation of cancer stem cells in triple negative breast cancer

Fultang¹,

Chakraborty²,

Peethambaran³

2021

CDR

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“…Hyperactive Hedgehog signalling has also been associated with many malignancies, such as OS and lung, colon, breast and pancreatic cancer 11‐16 . Functionally, Hedgehog signalling regulates cancer stemness and metastasis 17,18 .…”

Section: Introductionmentioning

confidence: 99%

“…Hyperactive Hedgehog signalling has also been associated with many malignancies, such as OS and lung, colon, breast and pancreatic cancer. 11 , 12 , 13 , 14 , 15 , 16 Functionally, Hedgehog signalling regulates cancer stemness and metastasis. 17 , 18 Gli1 is the major transcriptional activator in Hedgehog signalling and has been shown to mediate the activation of several Hedgehog target genes, including Hhip , Ptch1 , Cyclin D1 and Snail .…”

Section: Introductionmentioning

confidence: 99%

Gankyrin activates the hedgehog signalling to drive metastasis in osteosarcoma

Wang

Jing

et al. 2021

J Cellular Molecular Medi

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Gankyrin is a regulatory subunit of the 26‐kD proteasome complex and promotes the occurrence and progression of many malignancies. However, the role of gankyrin in osteosarcoma (OS) metastasis remains unclear. Hedgehog signalling has been shown to regulate stem cell homeostasis and cancer metastasis, but the mechanisms that activate this pathway in OS are still poorly understood. Here, a series of in vitro and in vivo assays were carried out to explore the function and mechanism of gankyrin regulating Hedgehog signalling in OS. We demonstrated that gankyrin promotes migration, invasion and regulates the expression of some stemness factors by up‐regulating Gli1 in OS. Importantly, our data showed an interaction between gankyrin and Gli1. Moreover, gankyrin suppresses the ubiquitin‐mediated degradation of Gli1 protein in OS. Gankyrin also significantly promotes the lung metastasis of OS in vivo. Our findings suggest that gankyrin drives metastasis and regulates the expression of some stemness factors in osteosarcoma by activating Hedgehog signalling, indicating that drug screening for compounds targeting gankyrin may contribute to the development of novel and effective therapies for OS.

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“…Clinically, we observed USP44 possessed a positive correlation with Itch expression but a negative correlation with Gli1 or PDL1 expression in HCC. In addition, the Gli1 inhibitor GANT61, which has previously been shown to inhibit the progression of several tumors (23,24), has been shown to signi cantly improves the anti-PDL1 e cacy in murine model. Nevertheless, future studies will be necessary to develop USP44 activator to con rm the anticarcinogenic role of USP44 in the progression of HCC.…”

Section: Discussionmentioning

confidence: 99%

Deubiquitinating enzyme USP44 suppresses hepatocellular carcinoma progression through inhibiting Hedgehog signaling and PDL1 expression

Xie,

Chen,

Zhou

et al. 2023

Preprint

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Hepatocellular carcinoma (HCC) is one of the deadliest malignancies in the world. Research into the key genes that maintain the malignant behavior of cancer cells is crucial for the treatment of HCC. Here, we identify ubiquitin‐specific peptidase 44 (USP44), a member of deubiquitinase family, as a novel regulator of HCC progression. The tumor suppressive function of USP44 was evaluated in a series of in vitro and in vivo experiments including using USP44 flox/flox mice and orthotopic xenograft models.Through Quantitative Proteomics examination, we demonstrated that USP44 inhibits HCC PDL1 expression through downregulating Hedgehog (Hh) signaling pathway. Mechanistically, we found USP44 directly interacts with Itch, an E3 ligase involved in Hh signaling, and promotes the deubiquitination and stabilization of Itch.These events result in the proteasomal degradationof Gli1 and subsequent inactivation of Hh signaling, which ultimately suppresses the PDL1 expression and progression of HCC. Furthermore, HCC tissue microarray was analyzed by immunohistochemistry to evaluate the pathological relevance of the USP44/Itch/Gli1/PDL1 axis. At last, Gli1 inhibitor GANT61 was found to act in synergy with anti-PDL1 therapy. Overall, USP44 can act as a suppressive gene in HCC by modulating Hh signaling and co-inhibition of Gli1 and PDL1 might be an effective novel combination strategy for treating HCC patients.

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Mesenchymal Cells Support the Oncogenicity and Therapeutic Response of the Hedgehog Pathway in Triple-Negative Breast Cancer

Cited by 9 publications

References 56 publications

Regulation of cancer stem cells in triple negative breast cancer

Regulation of cancer stem cells in triple negative breast cancer

Gankyrin activates the hedgehog signalling to drive metastasis in osteosarcoma

Deubiquitinating enzyme USP44 suppresses hepatocellular carcinoma progression through inhibiting Hedgehog signaling and PDL1 expression

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