Interferon-dependent SLC14A1+ cancer-associated fibroblasts promote cancer stemness via WNT5A in bladder cancer

Ma, Zhiyuan; Li, Xiangdong; Mao, Yijun; Chen, Wei; Huang, Zhuoli; Li, Guibo; Yin, Jianhua; Liang, Xiaoyu; Liu, Zhuowei

doi:10.1016/j.ccell.2022.11.005

Cited by 73 publications

(49 citation statements)

References 57 publications

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“…This could be due to the high angiogenic activity of CAF high cluster. Although our results suggested that the CAF high cluster was more sensitive to classical chemotherapeutic agents such as 5‐fluorouracil and doxorubicin, previous studies have shown that CAF induces tumor resistance to chemotherapeutic agents 43 . A study showed that the combination of a PD‐1 inhibitor and sorafenib effectively controlled HCC progression 44 .…”

Section: Discussionmentioning

confidence: 50%

“…Although our results suggested that the CAF high cluster was more sensitive to classical chemotherapeutic agents such as 5-fluorouracil and doxorubicin, previous studies have shown that CAF induces tumor resistance to chemotherapeutic agents. 43 A study showed that the combination of a PD-1 inhibitor and sorafenib effectively controlled HCC progression. 44 Therefore, the results of our analysis verified that combination therapy of PD-1 inhibitors and antiangiogenic drugs could effectively improve the prognosis of CAFs high cluster patients with HCC.…”

Section: Discussionmentioning

confidence: 99%

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Cancer‐associated fibroblasts contribute to the immunosuppressive landscape and influence the efficacy of the combination therapy of PD‐1 inhibitors and antiangiogenic agents in hepatocellular carcinoma

Chen

Wang

Zheng

et al. 2023

Cancer

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BackgroundChronic inflammation is considered the most critical predisposing factor of hepatocellular carcinoma (HCC), with inflammatory cell heterogeneity, hepatic fibrosis accumulation, and abnormal vascular proliferation as prominent features of the HCC tumor microenvironment (TME). Cancer‐associated fibroblasts (CAFs) play a key role in HCC TME remodeling. Therefore, the level of abundance of CAFs may significantly affect the prognosis and outcome in HCC patients.MethodsUnsupervised clustering was performed based on 39 genes related to CAFs in HCC identified by single‐cell RNA sequencing data. Patients of bulk RNA were grouped into CAF low abundance cluster and high abundance clusters. Subsequently, prognosis, immune infiltration landscape, metabolism, and treatment response between the two clusters were investigated and validated by immunohistochemistry.ResultsPatients in the CAF high cluster had a higher level of inflammatory cell infiltration, a more significant immunosuppressive microenvironment, and a significantly worse prognosis than those in the low cluster. At the metabolic level, the CAF high cluster had lower levels of aerobic oxidation and higher angiogenic scores. Drug treatment response prediction indicated that the CAF high cluster could have a better response to PD‐1 inhibitors and conventional chemotherapeutic agents for HCC such as anti‐angiogenic drugs, whereas CAF low cluster may be more sensitive to transarterial chemoembolization treatment.ConclusionsThis study not only revealed the TME characteristics of HCC with the difference in CAF abundance but also further confirmed that the combination therapy of PD‐1 inhibitors and anti‐angiogenic drugs may be more valuable for patients with high CAF abundance.

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Section: Discussionmentioning

confidence: 50%

Section: Discussionmentioning

confidence: 99%

Cancer‐associated fibroblasts contribute to the immunosuppressive landscape and influence the efficacy of the combination therapy of PD‐1 inhibitors and antiangiogenic agents in hepatocellular carcinoma

Chen

Wang

Zheng

et al. 2023

Cancer

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“…Parameters for FindAllMarkers included min.pct = 0.25, logfc.threshold = 0.75, and only pos = T. Non‐parametric Wilcoxon rank‐sum test was performed to calculate p‐values, with p‐values < 0.05 after Bonferroni correction considered significant. Established markers were used, [ 22 ] including epithelial cells ( EPCAM , KRT7 , and KRT13 positive), myeloid cells ( LYZ , CD68 , CD1E , and C1QB positive), fibroblast cells ( DCN , COL3A1 , and COL1A1 positive), T cells ( CD3D , CD3E , and CD2 positive), and endothelial cells ( PLVAP , VWF , and CLDN5 positive).…”

Section: Methodsmentioning

confidence: 99%

“…[19] Similarly, Liu et al reported a functional CAF subset in BC, known as interferon-regulated CAF, which enhances tumor stemness and mediates chemotherapy resistance by secreting WNT5A and interacting with tumor cells. [22] Targeting CAFs has shown the potential to improve chemotherapy sensitivity and reduce tumor recurrence. [6,23,24] Nonetheless, the heterogeneity of CAFs between primary and recurrent BC and the underlying mechanisms of BC recurrence are not fully understood.…”

Section: Introductionmentioning

confidence: 99%

Cancer‐Associated Fibroblast‐Induced Remodeling of Tumor Microenvironment in Recurrent Bladder Cancer

Liang,

Tao,

et al. 2023

Advanced Science

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Bladder carcinoma (BC) recurrence is a major clinical challenge, and targeting the tumor microenvironment (TME) is a promising therapy. However, the relationship between individual TME components, particularly cancer‐associated fibroblasts (CAFs), and tumor recurrence is unclear. Here, TME heterogeneity in primary and recurrent BC is investigated using single‐cell RNA sequence profiling of 62 460 cells. Two cancer stem cell (CSC) subtypes are identified in recurrent BC. An inflammatory CAF subtype, ICAM1+ iCAFs, specifically associated with BC recurrence is also identified. iCAFs are found to secrete FGF2, which acts on the CD44 receptor of rCSC‐M, thereby maintaining tumor stemness and epithelial‐mesenchymal transition. Additionally, THBS1+ monocytes, a group of myeloid‐derived suppressor cells (MDSCs), are enriched in recurrent BC and interacted with CAFs. ICAM1+ iCAFs are found to secrete CCL2, which binds to CCR2 in MDSCs. Moreover, elevated STAT3, NFKB2, VEGFA, and CTGF levels in iCAFs reshape the TME in recurrent tumors. CCL2 inhibition in an in situ BC mouse model suppressed tumor growth, decreased MDSCs and Tregs, and fostered tumor immune suppression. The study results highlight the role of iCAFs in TME cell–cell crosstalk during recurrent BC. The identification of pivotal signaling factors driving BC relapse is promising for the development of novel therapies.

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“…More recently, a novel CAF subset, SLC14A1 + CAFs, whose formation is induced by IFN signaling, was discovered in bladder cancer by scRNA-seq analyses, and through the activation of β-catenin in tumor cells, SLC14A1 + CAF-secreted WNT5A can promote cancer cell stemness, ultimately altering the effectiveness of chemotherapeutic drugs on cancer cells. 166 Drug resistance is challenging in cancer treatment. Exosomes derived from CAFs have been demonstrated to be involved in this process, as reviewed by Li et al 190 For example, gastric cancer is less sensitive to both cisplatin and paclitaxel.…”

Section: Key Genes Regulating Fibroblastmentioning

confidence: 99%

Targets of tumor microenvironment for potential drug development

Zhang,

Wang,

Liu

et al. 2024

MedComm – Oncology

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The tumor microenvironment (TME) is the ecosystem surrounding a tumor, which usually consists of nontumoral cells or components, and molecules they produce and release. The frequent and continuous interplay between tumor cells and the TME strongly affects tumor development, disease progression, metastasis, and responses to therapeutic interventions. As a hub of potential therapeutic targets, the TME has gained appreciable momentum in cancer research. Here we systematically review the progress in targeting the TME as a strategy to develop novel antitumor drugs from the immunological, stromal and extracellular matrix components of the TME, shedding light on its complex synergies with tumor cells. This exploration highlights the transformative potential these elements hold in refining cancer treatment approaches. This thorough examination not only accentuates the TME's multifaceted nature but also positions it as a formidable avenue for propelling forward the paradigms of cancer therapy. This review aims to foster a deeper understanding of the TME's role in oncogenesis and its potential exploitation in advancing targeted, efficacious cancer treatments, marking a significant stride in the realm of cancer research.

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Interferon-dependent SLC14A1+ cancer-associated fibroblasts promote cancer stemness via WNT5A in bladder cancer

Cited by 73 publications

References 57 publications

Cancer‐associated fibroblasts contribute to the immunosuppressive landscape and influence the efficacy of the combination therapy of PD‐1 inhibitors and antiangiogenic agents in hepatocellular carcinoma

Cancer‐associated fibroblasts contribute to the immunosuppressive landscape and influence the efficacy of the combination therapy of PD‐1 inhibitors and antiangiogenic agents in hepatocellular carcinoma

Cancer‐Associated Fibroblast‐Induced Remodeling of Tumor Microenvironment in Recurrent Bladder Cancer

Targets of tumor microenvironment for potential drug development

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