SPIN90 Depletion and Microtubule Acetylation Mediate Stromal Fibroblast Activation in Breast Cancer Progression

You, Eunae; Huh, Yun Hyun; Kwon, Ahreum; Kim, Sohee; Chae, In Hee; Lee, Ok Jun; Ryu, Je Hwang; Park, Min Ho; Kim, Ga-Eon; Lee, Ji Shin; Lee, Kun Ho; Lee, Yong Seok; Kim, Jung Woong; Rhee, Sangmyung; Song, Woo Keun

doi:10.1158/0008-5472.can-17-0657

Cited by 26 publications

(36 citation statements)

References 43 publications

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“…The inhibitory effects of irigenin in our in vivo mice model suggest a possible approach for overcoming limitations on the delivery of established anticancer drugs. Increased FN(+)EDA, appearing as aligned fibrils, was observed in the tumor stroma of 10 breast cancer patients in which SPIN90 downregulation was detected (You et al, ). This correlation between SPIN90 downregulation and FN(+)EDA expression suggests that FN(+)EDA contributes to the development of a stiff ECM in breast cancer stroma.…”

Section: Discussionmentioning

confidence: 99%

“…MEFs were isolated and immortalized as previously described (You et al, 2017) (Gapdh) and presented as fold change relative to the indicated controls. The following primers were used for RT-PCR and qRT-PCR.…”

Section: Cell Culturementioning

confidence: 99%

“…To test this, we employed irigenin, a specific competitive inhibitor that disrupts the interaction between FN (+)EDA and Integrin α4β1 (Amin et al, 2016). In our previous work, we found that Spin90-KO MEFs exhibited myofibroblast phenotypes, characterized by expression of α-SMA and cellular contractility (You et al, 2017). Irigenin treatment blocked phosphorylation of FAK, a kinase downstream of Integrin signaling, and reduced α-SMA expression in a concentration-dependent manner in Spin90-KO MEFs (Figure 2c).…”

Section: A Spin90 Deficiency Induces Fn(+)eda Expressionmentioning

confidence: 99%

“…In a previous study, we reported that SPIN90 (SH3 protein interacting with Nck, 90 kD; also known as NCKIPSD) is involved in CAF activation during breast cancer progression (You et al, ). Mouse embryonic fibroblasts (MEFs) derived from Spin90 ‐knockout (KO) mice exhibit CAF‐like phenotypes under low‐stiffness conditions that mimic the early stage of the breast cancer stroma.…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Extra domain A‐containing fibronectin expression in Spin90‐deficient fibroblasts mediates cancer‐stroma interaction and promotes breast cancer progression

Kwon

Chae

You

et al. 2019

Journal Cellular Physiology

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Cancer-associated fibroblasts (CAFs) in the tumor microenvironment play major roles in supporting cancer progression. A previous report showed that SPIN90 downregulation is correlated with CAF activation and that SPIN90-deficient CAFs promote breast cancer progression. However, the mechanisms that mediate cancer-stroma interaction and how such interactions regulate cancer progression are not well understood. Here, we show that extra domain A (EDA)-containing fibronectin (FN), FN(+)EDA, produced by mouse embryonic fibroblasts (MEFs) derived from Spin90knockout (KO) mice increases their own myofibroblast differentiation, which facilitates breast cancer progression. Increased FN(+)EDA in Spin90-KO MEFs promoted fibril formation in the extracellular matrix (ECM) and specifically interacted with integrin α4β1 as the mediating receptor. Moreover, FN(+)EDA expression by Spin90-KO MEFs increased proliferation, migration, and invasion of breast cancer cells. Irigenin, a specific inhibitor of the interaction between integrin α4β1 and FN(+) EDA, significantly blocked the effects of FN(+)EDA, such as fibril formation by Spin90-KO MEFs and proliferation, migration, and invasion of breast cancer cells. In orthotopic breast cancer mouse models, irigenin injection remarkably reduced tumor growth and lung metastases. It was supported by that FN(+)EDA in assembled fibrils was accumulated in cancer stroma of human breast cancer patients in which SPIN90 expression was downregulated. Our data suggest that SPIN90 downregulation increases FN(+)EDA and promotes ECM stiffening in breast cancer stroma through an assembly of long FN(+)EDA-rich fibrils; moreover, engagement of the Integrin α4β1 receptor facilitates breast cancer progression. Inhibitory effects of irigenin on tumor growth and metastasis suggest the potential of this agent as an anticancer therapeutic. K E Y W O R D S cancer-associated fibroblast, extracellular matrix, FN(+)EDA, SPIN90, tumor microenvironment Breast cancer tissues with adjacent normal epithelial tissues of Human patients were kindly supplied and analyzed by Chungbuk

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Section: Discussionmentioning

confidence: 99%

Section: Cell Culturementioning

confidence: 99%

Section: A Spin90 Deficiency Induces Fn(+)eda Expressionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Extra domain A‐containing fibronectin expression in Spin90‐deficient fibroblasts mediates cancer‐stroma interaction and promotes breast cancer progression

Kwon

Chae

You

et al. 2019

Journal Cellular Physiology

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Signaling pathways in cancer‐associated fibroblasts: recent advances and future perspectives

Fang

Meng

et al. 2022

Cancer Communications

101

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As a critical component of the tumor microenvironment (TME), cancer‐associated fibroblasts (CAFs) play important roles in cancer initiation and progression. Well‐known signaling pathways, including the transforming growth factor‐β (TGF‐β), Hedgehog (Hh), Notch, Wnt, Hippo, nuclear factor kappa‐B (NF‐κB), Janus kinase (JAK)/signal transducer and activator of transcription (STAT), mitogen‐activated protein kinase (MAPK), and phosphoinositide 3‐kinase (PI3K)/AKT pathways, as well as transcription factors, including hypoxia‐inducible factor (HIF), heat shock transcription factor 1 (HSF1), P53, Snail, and Twist, constitute complex regulatory networks in the TME to modulate the formation, activation, heterogeneity, metabolic characteristics and malignant phenotype of CAFs. Activated CAFs remodel the TME and influence the malignant biological processes of cancer cells by altering the transcriptional and secretory characteristics, and this modulation partially depends on the regulation of signaling cascades. The results of preclinical and clinical trials indicated that therapies targeting signaling pathways in CAFs demonstrated promising efficacy but were also accompanied by some failures (e.g., NCT01130142 and NCT01064622). Hence, a comprehensive understanding of the signaling cascades in CAFs might help us better understand the roles of CAFs and the TME in cancer progression and may facilitate the development of more efficient and safer stroma‐targeted cancer therapies. Here, we review recent advances in studies of signaling pathways in CAFs and briefly discuss some future perspectives on CAF research.

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Modulating the acetylation of α‐tubulin by LncRNAs and microRNAs helps in the progression of cancer

Kar,

Mukherjee,

Guha

et al. 2024

Cell Biochemistry & Function

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Malignant tumor cells go through morphological and gene expression alterations, including rearrangement of cytoskeleton proteins that promote invasion and metastasis. Microtubules form a major cytoskeleton component that plays a significant role in regulating multiple cellular activities and function depending on the presence of posttranslational modification (PTM). Acetylation is a type of PTM that generally occurs in the lysine 40 region of α‐tubulin and is known to be critically associated with cancer metastasis. Current evidence demonstrates that noncoding RNAs, such as long noncoding RNA (lncRNA) and microRNA (or miRNA), which are correlated with gene regulation modulate the expression of acetylated tubulin in the development and metastasis of cancer. This review provides an overview about the role of lncRNA and miRNA in regulation of tubulin acetylation in various types of cancer.

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SPIN90 Depletion and Microtubule Acetylation Mediate Stromal Fibroblast Activation in Breast Cancer Progression

Cited by 26 publications

References 43 publications

Extra domain A‐containing fibronectin expression in Spin90‐deficient fibroblasts mediates cancer‐stroma interaction and promotes breast cancer progression

Extra domain A‐containing fibronectin expression in Spin90‐deficient fibroblasts mediates cancer‐stroma interaction and promotes breast cancer progression

Signaling pathways in cancer‐associated fibroblasts: recent advances and future perspectives

Modulating the acetylation of α‐tubulin by LncRNAs and microRNAs helps in the progression of cancer

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