CD26-negative and CD26-positive tissue-resident fibroblasts contribute to functionally distinct CAF subpopulations in breast cancer

Houthuijzen, Julia M.; Bruijn, Roebi de; Burg, Eline van der; Drenth, Anne Paulien; Wientjens, Ellen; Filipovic, Tamara; Bullock, Esme; Brambillasca, Chiara Svetlana; Pulver, Emilia; Nieuwland, Marja; Rink, Iris de; Diepen, Frank van; Klarenbeek, Sjoerd; Kerkhoven, Ron; Brunton, Valerie G.; Scheele, Colinda L.G.J.; Boelens, Mirjam C.; Jonkers, Jos

doi:10.1038/s41467-023-35793-w

Cited by 34 publications

(26 citation statements)

References 69 publications

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“…Supported by our finding that NRF2 and the OSR are high in iCAFs, and since it was suggested that normal fibroblasts likely give rise to iCAFs (Houthuijzen et al , 2023), we hypothesized that NRF2 either regulates the transition of normal fibroblasts to iCAF, the transition from iCAFs to myCAFs, or both. To test this hypothesis, we performed trajectory analysis of two of the scRNA- seq datasets we analyzed, which also contained normal samples of breast and pancreatic tissues (Pal et al , 2021; Peng et al , 2019)(Figure 6F-J,K-O).…”

Section: Resultsmentioning

confidence: 71%

Mapping the tumor stress network reveals dynamic shifts in the stromal oxidative stress response

Lior,

Barki,

Iacobuzio-Donahue

et al. 2023

Preprint

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The tumor microenvironment (TME) is a challenging environment where cells must cope with stressful conditions such as fluctuating pH levels, hypoxia, and free radicals. In response, stress pathways are activated, which can both promote and inhibit tumorigenesis. In this study, we set out to characterize the stress response landscape across four carcinomas: breast, pancreas, ovary, and prostate tumors, focusing on five pathways: Heat shock response, oxidative stress response, unfolded protein response, hypoxia stress response, and DNA damage response. Using a combination of experimental and computational methods, we create an atlas of the stress response landscape across various types of carcinomas. We find that stress responses are heterogeneously activated in the TME, and highly activated near cancer cells. Focusing on the non-immune stroma we find, across tumor types, that NRF2 and the oxidative stress response are distinctly activated in immune-regulatory cancer-associated fibroblasts and in a unique subset of cancer associated pericytes. Our study thus provides an interactome of stress responses in cancer, offering new ways to intersect survival pathways within the tumor, and advance cancer therapy.

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Section: Resultsmentioning

confidence: 71%

Mapping the tumor stress network reveals dynamic shifts in the stromal oxidative stress response

Lior,

Barki,

Iacobuzio-Donahue

et al. 2023

Preprint

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“…In this work, we utilized scRNA-seq in combination with bulk transcriptome data for systematically analyzing the cell components within the tumor microenvironment of TNBC. Tumorigenesis is governed both by genetically altered tumor cells and non-malignant host cells within the tumor microenvironment, extensively impacting tumor progression, metastases, and therapeutic outcomes [39]. We reported that the tumor microenvironment of TNBC was composed of B cells, dendritic cells, endothelial cells, epithelial cells, fibroblasts, macrophages, monocytes, plasmablasts, and T cells.…”

Section: Discussionmentioning

confidence: 99%

Integration of single-cell and bulk transcriptome analyses unravels a macrophage-based gene signature for prognostication and treatment in triple-negative breast cancer

Huang,

Yu,

Zhang

et al. 2023

Preprint

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Objective As a dominant component within the tumor microenvironment, macrophages exert an essential role in almost all aspects of triple-negative breast cancer (TNBC). This work explored macrophage-associated signature genes for prognostication and treatment for TNBC. Methods Single-cell (GSE180286) and bulk transcriptome profiles (TCGA-TNBC, GSE96058 and GSE45255) were analyzed by executing multiple computational approaches. The expression of signature genes was verified in breast cancer cells (MDA-MB-231, and MCF-7) and mammary epithelial cells (MCF10A) through RT-qPCR and western blot. After RNA interference or overexpression, wound scratch assay was implemented. Results A single-cell map of the microenvironment of non-TNBC and TNBC was depicted. Both at the single-cell and bulk levels, macrophages exhibited the higher abundance in TNBC versus non-TNBC. A macrophage-based gene signature was built, containing CTSD, CTSL, ELK4, HSPA8, and XRCC4. High risk score was predictive of worse prognostic outcomes. Based upon external validation, the signature could reliably predict patient prognosis, notably one-year survival. High-risk patients were more responsive to immunotherapy. The aberrant expression of CTSD, CTSL, ELK4, HSPA8, and XRCC4 was proven in breast cancer cells and mammary epithelial cells. Knockdown of XRCC4 attenuated migrative abilities of MDA-MB-231, MCF-7, and MCF10A cells, with opposite findings for overexpressed CTSD, CTSL, and HSPA8. Conclusions Altogether, a novel macrophage-based gene signature was proposed for estimating survival outcomes and treatment response in TNBC. The aberrant expression of the signature genes contributed to tumor aggressiveness. Our findings exert a positive impact on future clinical research involving macrophages in TNBC.

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“…Unlike other clusters, cluster 4 CAFs were not enriched for "extracellular matrix structural constituent" (Figure 1F), suggesting that cluster 4 CAFs were not the main contributor to ECM (extracellular matrix) structure. Cluster 5 CAFs predominantly expressed cytokine Cxcl12, which is expressed in the iCAF subset and involved in myeloid cell recruitment 23 . Taken together, our data suggest the presence of distinct subsets of CAFs in WT and LATS1/2 dKO breast tumors.…”

Section: Single-cell Rna Sequencing (Scrna-seq) Analysis Reveals Dist...mentioning

confidence: 99%

Hippo pathway in cancer cells modulates tumor microenvironment by inducing immunosuppressive NCAM1+αSMA+ fibroblasts

Moroishi,

Thinyakul,

Sakamoto

et al. 2024

Preprint

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Tumor cells adeptly manipulate the tumor microenvironment (TME) to evade host antitumor immunity. However, the role of tumor cell-intrinsic signaling in shaping the immunosuppressive TME remains unclear. Here, we found that the Hippo pathway in tumor cells orchestrated the immunosuppressive TME by influencing the composition of cancer-associated fibroblasts (CAFs). In a 4T1 mouse breast cancer model, Hippo pathway kinases, large tumor suppressor 1 and 2 (LATS1/2), promoted the formation of immunosuppressive neural cell adhesion molecule 1 (NCAM1)+alpha-smooth muscle actin (αSMA)+ CAFs expressing the transforming growth factor-β, thereby contributing to T cell dysfunction. Depletion of LATS1/2 in tumor cells resulted in a less immunosuppressive TME, indicated by the reduced proportions of NCAM1+αSMA+ CAFs and dysfunctional T cells. Notably, similar Hippo pathway-induced NCAM1+αSMA+ CAFs were observed in human breast cancer cells, highlighting the potential of TME-manipulating strategies to reduce immunosuppression in cancer immunotherapy.

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CD26-negative and CD26-positive tissue-resident fibroblasts contribute to functionally distinct CAF subpopulations in breast cancer

Cited by 34 publications

References 69 publications

Mapping the tumor stress network reveals dynamic shifts in the stromal oxidative stress response

Mapping the tumor stress network reveals dynamic shifts in the stromal oxidative stress response

Integration of single-cell and bulk transcriptome analyses unravels a macrophage-based gene signature for prognostication and treatment in triple-negative breast cancer

Hippo pathway in cancer cells modulates tumor microenvironment by inducing immunosuppressive NCAM1+αSMA+ fibroblasts

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