Microenvironmental control of cell fate decisions in mammary gland development and cancer

Rauner, Gat; Kuperwasser, Charlotte

doi:10.1016/j.devcel.2021.06.016

Cited by 20 publications

(12 citation statements)

References 135 publications

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“…Correspondingly, E2 treatment induced the upregulation of known IFN-regulated genes (e.g., Ifi27l2a, Cxcl10 ) in the Dpp4 + fibroblasts. Cxcl10 is a known regulator of immune microenvironment to drive migration and activation of immune cells, including macrophages ( Tokunaga et al, 2018 ), which is also an important player for successful mammary gland morphogenesis ( Rauner and Kuperwasser, 2021 ). Furthermore, the upregulated genes in the Dpp4 + fibroblasts included immune modulatory or angiogenic factors such as Ccl8 , Lgals1 , and Figf .…”

Section: Discussionmentioning

confidence: 99%

Single-Cell Transcriptomics Identifies Heterogeneity of Mouse Mammary Gland Fibroblasts With Distinct Functions, Estrogen Responses, Differentiation Processes, and Crosstalks With Epithelium

Yoshitake

Chang

Saeki

et al. 2022

Front. Cell Dev. Biol.

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Fibroblasts have been shown to be one of the essential players for mammary gland organization. Here, we identify two major types of mouse mammary gland fibroblasts through single-cell RNA sequencing analysis: Dpp4+ fibroblasts and Dpp4- fibroblasts. Each population exhibits unique functional characteristics as well as discrete localization in normal mouse mammary glands. Remarkably, estrogen, a crucial mediator of mammary gland organization, alters the gene expression profiles of fibroblasts in a population-specific manner, without distinct activation of estrogen receptor signaling. Further integrative analysis with the inclusion of five other publicly available datasets reveals a directional differentiation among the mammary gland fibroblast populations. Moreover, the combination with the mouse mammary epithelium atlas allows us to infer multiple potential interactions between epithelial cells and fibroblasts in mammary glands. This study provides a comprehensive view of mouse mammary gland fibroblasts at the single-cell level.

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Section: Discussionmentioning

confidence: 99%

Single-Cell Transcriptomics Identifies Heterogeneity of Mouse Mammary Gland Fibroblasts With Distinct Functions, Estrogen Responses, Differentiation Processes, and Crosstalks With Epithelium

Yoshitake

Chang

Saeki

et al. 2022

Front. Cell Dev. Biol.

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“…The TME is mainly composed of various immune cells, vascular endothelial cells, and fibroblasts, which generate permissive niches for tumor progression (19). Heterogeneous features of the TME determine both the diverse fates and drug responses of tumors, and the TME also has strong predictive value for tumor prognosis (20). In particular, the importance of immune cell populations, reflecting the capacity of the immune system to sense tumor cells, has been recognized for prognosis (21).…”

Section: Discussionmentioning

confidence: 99%

Anti-Tumor Role of CAMK2B in Remodeling the Stromal Microenvironment and Inhibiting Proliferation in Papillary Renal Cell Carcinoma

et al. 2022

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The tumor microenvironment (TME) is variable across tumor types and has diverse effects on malignant progression, based on the type and number of infiltrating stromal cells. In particular, TME effector genes and their competitive endogenous RNA (ceRNA) networks play a critical role in regulating malignant tumor progression. However, the core effector molecules involved in TME modulation of kidney renal papillary cell carcinoma (KIRP) are poorly understood. To address this question, a cohort containing 233 KIRP patients was derived from The Cancer Genome Atlas (TCGA) database, and the data were processed using the ESTIMATE algorithm. We further evaluated the relationship between immune scores (ISs) and stromal scores (SSs) and disease progression and found that high SSs were associated with a poor prognosis in KIRP. Differentially expressed genes (DEGs) were therefore screened based on SS scores, resulting in 2509 DEGs, including 1668 mRNAs, 783 long noncoding (lnc)RNAs, and 58 micro (mi)RNAs. DEGs were then filtered using the random variance and subjected to hierarchical clustering using EPCLUST. Weighted gene co-expression network analysis (WGCNA) was used to assess the prognostic capacity of these DEGs and identify target ceRNA networks, and lncRNA GUSBP11/miR-432-5p/CAMK2B in the turquoise module was selected as a promising ceRNA network. From this analysis CAMK2B was selected as the core gene predicted to be involved in stromal TMA regulation. We therefore explored the expression and function of CAMK2B in vitro and in vivo and provide evidence that this protein promotes stromal TME remodulation and inhibits proliferation in KIRP. Lastly, we show that vascular endothelial growth factor (VEGF), transforming growth factor (TGF)β, and close homolog of L1 (CHL1) act as downstream effectors of CAMK2B in KIRP. Thus, in this study, we show that the TME determines prognosis of KIRP patients via the core effector molecule CAMK2B, which mediates both microenvironmental remodeling and tumor progression. Based on these findings, we propose that remodeling of the stromal microenvironment could represent an improved therapeutic approach relative to immunotherapy for KIRP.

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“…The role of ECM in tumor progression is getting more and more attention. 22 In the dynamic balance of ECM, small changes can have a significant impact on tumor cell proliferation, migration, invasion, and apoptosis. 23 We found that multiple MMPs enriched in the ECM were related to RCN3 expression.…”

Section: Discussionmentioning

confidence: 99%

Reticulocalbin3: A Ca²⁺ homeostasis regulator that promotes esophageal squamous cell carcinoma progression and cisplatin resistance

et al. 2022

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Esophageal squamous cell carcinoma (ESCC) is one of the most prevalent cancers worldwide. There is a critical need to identify new mechanisms that contribute to ESCC progression. Reticulocalbin3 (RCN3) is mainly located in the endoplasmic reticulum and Ca2+‐binding protein containing EF‐hands. The function of RCN3 in tumor progression has not been clarified. We observed that the expression level of RCN3 was higher in ESCC tissues than in paired normal tissues. Overexpression of RCN3 was positively associated with tumor size, lymph node metastasis, TNM stage, lymphatic vessel infiltration, and poor outcome in patients with ESCC. Increased malignant phenotypes were observed in RCN3 overexpressing ESCC cells, whereas the opposite effects were achieved in RCN3‐silenced cells. Reticulocalbin3 promoted the expression of MMP‐2 and MMP‐9 by regulating the inositol 1,4,5‐trisphosphate receptor 1 (IP3R1)–Ca2+–calcium/calmodulin‐dependent protein kinase II–c‐Jun signaling pathway. Reticulocalbin3 induced cisplatin resistance by regulating IP3R1/Ca2+ to maintain intracellular Ca2+ homeostasis and reduced reactive oxygen species in ESCC cells. Finally, the expression of RCN3 was regulated by hypoxia inducible factor‐1α. Collectively, these data strongly support that RCN3 regulates Ca2+ homeostasis by targeting IP3R1 to promote the progression and platinum resistance of ESCC. Our studies suggest that RCN3 could serve as predictive factor of poor prognosis and potential therapeutic target for ESCC patients.

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Microenvironmental control of cell fate decisions in mammary gland development and cancer

Cited by 20 publications

References 135 publications

Single-Cell Transcriptomics Identifies Heterogeneity of Mouse Mammary Gland Fibroblasts With Distinct Functions, Estrogen Responses, Differentiation Processes, and Crosstalks With Epithelium

Single-Cell Transcriptomics Identifies Heterogeneity of Mouse Mammary Gland Fibroblasts With Distinct Functions, Estrogen Responses, Differentiation Processes, and Crosstalks With Epithelium

Anti-Tumor Role of CAMK2B in Remodeling the Stromal Microenvironment and Inhibiting Proliferation in Papillary Renal Cell Carcinoma

Reticulocalbin3: A Ca²⁺ homeostasis regulator that promotes esophageal squamous cell carcinoma progression and cisplatin resistance

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Microenvironmental control of cell fate decisions in mammary gland development and cancer

Cited by 20 publications

References 135 publications

Single-Cell Transcriptomics Identifies Heterogeneity of Mouse Mammary Gland Fibroblasts With Distinct Functions, Estrogen Responses, Differentiation Processes, and Crosstalks With Epithelium

Single-Cell Transcriptomics Identifies Heterogeneity of Mouse Mammary Gland Fibroblasts With Distinct Functions, Estrogen Responses, Differentiation Processes, and Crosstalks With Epithelium

Anti-Tumor Role of CAMK2B in Remodeling the Stromal Microenvironment and Inhibiting Proliferation in Papillary Renal Cell Carcinoma

Reticulocalbin3: A Ca2+ homeostasis regulator that promotes esophageal squamous cell carcinoma progression and cisplatin resistance

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Reticulocalbin3: A Ca²⁺ homeostasis regulator that promotes esophageal squamous cell carcinoma progression and cisplatin resistance