Promotion of cholangiocarcinoma growth by diverse cancer-associated fibroblast subpopulations

Affò, Silvia; Nair, Ajay; Brundu, Francesco; Ravichandra, Aashreya; Bhattacharjee, Sonakshi; Matsuda, Michitaka; Chin, Li Kang; Filliol, Aveline; Wen, Wen; Song, Xinhua; Decker, Aubrianna; Worley, Jeremy; Caviglia, Jorge Matías; Yu, Le-Xing; Yin, David; Saito, Yoshinobu; Savage, Thomas; Wells, Rebecca G.; Mack, Matthias; Zender, Lars; Arpaia, Nicholas; Remotti, Helen; Rabadán, Raúl; Sims, Peter A.; Leblond, Anne-Laure; Weber, Achim; Riener, Marc‐Oliver; Stockwell, Brent R.; Gaublomme, Jellert T.; Llovet, Josep M.; Kalluri, Raghu; Michalopoulos, George K.; Seki, Ekihiro; Sia, Daniela; Chen, Xin; Califano, Andrea; Schwabe, Robert F.

doi:10.1016/j.ccell.2021.05.010

Cited by 47 publications

(40 citation statements)

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“…The liver TME is composed of liver resident cells such as liver sinusoidal endothelial cells, HSCs, and Kupffer cells [35] and of other cell types such as myeloid-derived suppressor cells, regulatory T-cells, tumour-associated macrophages, and cancer-associated fibroblasts (CAFs) [39,40]. Recent studies have shown that HSCs are the major source of CAFs in liver cancer, although a small portion of the CAFs can be derived from other cell types, as shown in Figure 1 [9,41]. In conclusion, CAFs appear to be involved in every step of liver cancer development.…”

Section: Role Of Microenvironment In Liver Tumour Developmentmentioning

confidence: 99%

“…Because of the poor definition of CAFs, many researchers choose to use HSCs instead of CAFs when studying the role of fibroblasts in liver cancer (see sections 5 and 6). Recently, it was demonstrated that HSC-derived CAFs are essential for the production and remodelling of ECM in liver tumours [9,42]. An injured liver is characterized by the accumulation of ECM, which is composed of type I and III fibrillar collagens, fibronectin, undulin, laminin, hyaluronan, elastin, and proteoglycans [43].…”

Section: Definition and Use Of Cafs For In Vitro Liver Cancer Studiesmentioning

confidence: 99%

“…Recently, it was demonstrated that HSC-derived CAFs are essential for the production and remodelling of ECM in liver tumours [ 9 , 42 ]. An injured liver is characterized by the accumulation of ECM, which is composed of type I and III fibrillar collagens, fibronectin, undulin, laminin, hyaluronan, elastin, and proteoglycans [ 43 ].…”

Section: Role Of Microenvironment In Liver Tumour Developmentmentioning

confidence: 99%

“…These aHSCs express PDGF-bb, TGF-β, IL-6 and IL-1b. While liver CAFs do present with an increased expression of HGF, FGF, and VEGF, when compared to aHSCs [ 68 ], pan-CAF markers that were recently used for cluster definition on single cell RNA sequencing (sc-RNA seq) data include only genes that are also highly expressed by non-tumour- associated HSCs (Schwabe, Pan-CAF signature: Col1a1, Col1a2, Col3a1, C1s1, Acta2, C1ra, Serpinf1, Pdgfrβ, Col12a1) [ 9 , 11 ]. Because of the poor definition of CAFs, many researchers choose to use HSCs instead of CAFs when studying the role of fibroblasts in liver cancer (see Section 5 and Section 6 ).…”

Section: Definition and Use Of Cafs For In Vitro Liver Cancer Studiesmentioning

confidence: 99%

“…A better understanding of the underlying molecular mechanisms that drive tumour progression and metastasis could provide us with new treatment options. As the malignant behaviour of tumour cells can be greatly modulated by the tumour microenvironment (TME), knowledge about and targeting of the TME offers new therapeutic opportunities [ 7 , 8 , 9 , 10 , 11 , 12 ].…”

Section: Introductionmentioning

confidence: 99%

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Review: Challenges of In Vitro CAF Modelling in Liver Cancers

Herrero

Knetemann

Mannaerts

2021

Cancers

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Primary and secondary liver cancer are the third cause of death in the world, and as the incidence is increasing, liver cancer represents a global health burden. Current treatment strategies are insufficient to permanently cure patients from this devastating disease, and therefore other approaches are under investigation. The importance of cancer-associated fibroblasts (CAFs) in the tumour microenvironment is evident, and many pre-clinical studies have shown increased tumour aggressiveness in the presence of CAFs. However, it remains unclear how hepatic stellate cells are triggered by the tumour to become CAFs and how the recently described CAF subtypes originate and orchestrate pro-tumoural effects. Specialized in vitro systems will be needed to address these questions. In this review, we present the currently used in vitro models to study CAFs in primary and secondary liver cancer and highlight the trend from using oversimplified 2D culture systems to more complex 3D models. Relatively few studies report on the impact of cancer (sub)types on CAFs and the tumour microenvironment, and most studies investigated the impact of secreted factors due to the nature of the models.

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Section: Role Of Microenvironment In Liver Tumour Developmentmentioning

confidence: 99%

Section: Definition and Use Of Cafs For In Vitro Liver Cancer Studiesmentioning

confidence: 99%

Section: Role Of Microenvironment In Liver Tumour Developmentmentioning

confidence: 99%

Section: Definition and Use Of Cafs For In Vitro Liver Cancer Studiesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Review: Challenges of In Vitro CAF Modelling in Liver Cancers

Herrero

Knetemann

Mannaerts

2021

Cancers

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Cellular senescence and the tumour microenvironment

2022

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The senescence‐associated secretory phenotype (SASP), where senescent cells produce a variety of secreted proteins including inflammatory cytokines, chemokines, matrix remodelling factors, growth factors and so on, plays pivotal but varying roles in the tumour microenvironment. The effects of SASP on the surrounding microenvironment depend on the cell type and process of cellular senescence induction, which is often associated with innate immunity. Via SASP‐mediated paracrine effects, senescent cells can remodel the surrounding tissues by modulating the character of adjacent cells, such as stromal, immune cells, as well as cancer cells. The SASP is associated with both tumour‐suppressive and tumour‐promoting effects, as observed in senescence surveillance effects (tumour‐suppressive) and suppression of anti‐tumour immunity in most senescent cancer‐associated fibroblasts and senescent T cells (tumour‐promoting). In this review, we discuss the features and roles of senescent cells in tumour microenvironment with emphasis on their context‐dependency that determines whether they promote or suppress cancer development. Potential usage of recently developed drugs that suppress the SASP (senomorphics) or selectively kill senescence cells (senolytics) in cancer therapy are also discussed.

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Identification and validation of a lactate metabolism-related six-gene prognostic signature in intrahepatic cholangiocarcinoma

Sang,

Yan,

Lin

et al. 2024

J Cancer Res Clin Oncol

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Purpose Intrahepatic cholangiocarcinoma (iCCA) is a highly malignant and fatal liver tumor with increasing incidence worldwide. Lactate metabolism has been recently reported as a crucial contributor to tumor progression and immune regulation in the tumor microenvironment. However, it remains poorly identified about the biological functions of lactate metabolism in iCCA, which hinders the development of prognostic tools and therapeutic interventions. Methods The univariate Cox regression analysis and Boruta algorithm were utilized to identify key lactate metabolism-related genes (LMRGs), and a prognostic signature was constructed based on LMRG scores. Genomic variations and immune cell infiltration were evaluated in the high and low LMRG score groups. Finally, the biological functions of key LMRGs were verified with in vitro and in vivo experiments. Results Patients in the high LMRG score group exhibit a poor prognosis compared to those in the low LMRG score group, with a high frequency of TP53 and KRAS mutations. Moreover, the infiltration and function of NK cells were compromised in the high LMRG score group, consistent with the results from two independent single-cell RNA sequencing datasets and immunohistochemistry of tissue microarrays. Experimental data revealed that lactate dehydrogenase A (LDHA) knockdown inhibited proliferation and migration in iCCA cell lines and tumor growth in immunocompetent mice. Conclusion Our study revealed the biological roles of LDHA in iCCA and developed a reliable lactate metabolism-related prognostic signature for iCCA, offering promising therapeutic targets for iCCA in the clinic.

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Promotion of cholangiocarcinoma growth by diverse cancer-associated fibroblast subpopulations

Cited by 47 publications

References 0 publications

Review: Challenges of In Vitro CAF Modelling in Liver Cancers

Review: Challenges of In Vitro CAF Modelling in Liver Cancers

Cellular senescence and the tumour microenvironment

Identification and validation of a lactate metabolism-related six-gene prognostic signature in intrahepatic cholangiocarcinoma

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