Single-cell analysis defines a pancreatic fibroblast lineage that supports anti-tumor immunity

Hutton, Colin; Heider, Felix; Blanco-Gómez, Adrián; Banyard, Antonia; Kononov, Alexander; Zhang, Xiaohong; Karim, Saadia A.; Paulus-Hock, Viola; Watt, Dale; Steele, Nina G.; Kemp, Samantha B.; Hogg, Elizabeth; Kelly, Jane; Jackstadt, Rene-Filip; Lopes, Filipa; Menotti, Matteo; Chisholm, Luke; Lamarca, Ángela; Valle, Juan W.; Sansom, Owen J.; Springer, Caroline J.; Malliri, Angeliki; Marais, Richard; Magliano, Marina Pasca di; Zelenay, Santiago; Morton, Jennifer P.; Jørgensen, Claus

doi:10.1016/j.ccell.2021.06.017

Cited by 179 publications

(132 citation statements)

References 92 publications

(136 reference statements)

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“…Characteristics of the established myCAF and iCAF populations were found in either lineage, whereas all apCAF were CD105-. In contrast to myCAF and iCAF populations, CD105+ and CD105-pancreatic fibroblasts seemed not to be interconvertible [71].…”

Section: Et Al Distinguished Two Groups Of Pancreatic Myofibroblastsmentioning

confidence: 77%

The Heterogeneity of the Tumor Microenvironment as Essential Determinant of Development, Progression and Therapy Response of Pancreatic Cancer

Wandmacher

Mehdorn

Sebens

2021

Cancers

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Pancreatic ductal adenocarcinoma (PDAC) is commonly diagnosed at advanced stages and most anti-cancer therapies have failed to substantially improve prognosis of PDAC patients. As a result, PDAC is still one of the deadliest tumors. Tumor heterogeneity, manifesting at multiple levels, provides a conclusive explanation for divergent survival times and therapy responses of PDAC patients. Besides tumor cell heterogeneity, PDAC is characterized by a pronounced inflammatory stroma comprising various non-neoplastic cells such as myofibroblasts, endothelial cells and different leukocyte populations which enrich in the tumor microenvironment (TME) during pancreatic tumorigenesis. Thus, the stromal compartment also displays a high temporal and spatial heterogeneity accounting for diverse effects on the development, progression and therapy responses of PDAC. Adding to this heterogeneity and the impact of the TME, the microbiome of PDAC patients is considerably altered. Understanding this multi-level heterogeneity and considering it for the development of novel therapeutic concepts might finally improve the dismal situation of PDAC patients. Here, we outline the current knowledge on PDAC cell heterogeneity focusing on different stromal cell populations and outline their impact on PDAC progression and therapy resistance. Based on this information, we propose some novel concepts for treatment of PDAC patients.

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Section: Et Al Distinguished Two Groups Of Pancreatic Myofibroblastsmentioning

confidence: 77%

The Heterogeneity of the Tumor Microenvironment as Essential Determinant of Development, Progression and Therapy Response of Pancreatic Cancer

Wandmacher

Mehdorn

Sebens

2021

Cancers

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“…These CD105-expressing CAFs were more abundant than their CD105-non-expressing counterparts, were transcriptionally more responsive to TGFβ signaling, and demonstrated facilitated tumor growth in vivo. As these phenotypic differences appeared to be independent of myCAF and iCAF markers, CAF heterogeneity warrants additional study, as do the contributions of TGFβ signals to mesenchymal cell biology in PDAC [138].…”

Section: Tgfβ In Fibrosis and Stromal Cell Biologymentioning

confidence: 97%

TGFβ Signaling in the Pancreatic Tumor Microenvironment

Principe

Timbers

Atia

et al. 2021

Cancers

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Pancreatic ductal adenocarcinoma (PDAC) is associated with poor clinical outcomes, largely attributed to incomplete responses to standard therapeutic approaches. Recently, selective inhibitors of the Transforming Growth Factor β (TGFβ) signaling pathway have shown early promise in the treatment of PDAC, particularly as a means of augmenting responses to chemo- and immunotherapies. However, TGFβ is a potent and pleiotropic cytokine with several seemingly paradoxical roles within the pancreatic tumor microenvironment (TME). Although TGFβ signaling can have potent tumor-suppressive effects in epithelial cells, TGFβ signaling also accelerates pancreatic tumorigenesis by enhancing epithelial-to-mesenchymal transition (EMT), fibrosis, and the evasion of the cytotoxic immune surveillance program. Here, we discuss the known roles of TGFβ signaling in pancreatic carcinogenesis, the biologic consequences of the genetic inactivation of select components of the TGFβ pathway, as well as past and present attempts to advance TGFβ inhibitors in the treatment of PDAC patients.

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“…Another prominent study described a mass cytometry approach that allowed the analysis of mesenchymal stroma in both normal and tumor murine pancreatic tissues ( Hutton et al, 2021 ). The findings of this study revealed extensive stromal heterogeneity across both tissues and led to the identification of coordinated relationships between mesenchymal and immune cell subsets in PDAC.…”

Section: The Contributions Of Single Cell Sequencing (Scrna-seq) Technology To Cancer-associated Fibroblast Identificationmentioning

confidence: 99%

The Cellular Origins of Cancer-Associated Fibroblasts and Their Opposing Contributions to Pancreatic Cancer Growth

Manoukian

Bijlsma

Laarhoven

2021

Front. Cell Dev. Biol.

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Pancreatic tumors are known to harbor an abundant and highly desmoplastic stroma. Among the various cell types that reside within tumor stroma, cancer-associated fibroblasts (CAFs) have gained a lot of attention in the cancer field due to their contributions to carcinogenesis and tumor architecture. These cells are not a homogeneous population, but have been shown to have different origins, phenotypes, and contributions. In pancreatic tumors, CAFs generally emerge through the activation and/or recruitment of various cell types, most notably resident fibroblasts, pancreatic stellate cells (PSCs), and tumor-infiltrating mesenchymal stem cells (MSCs). In recent years, single cell transcriptomic studies allowed the identification of distinct CAF populations in pancreatic tumors. Nonetheless, the exact sources and functions of those different CAF phenotypes remain to be fully understood. Considering the importance of stromal cells in pancreatic cancer, many novel approaches have aimed at targeting the stroma but current stroma-targeting therapies have yielded subpar results, which may be attributed to heterogeneity in the fibroblast population. Thus, fully understanding the roles of different subsets of CAFs within the stroma, and the cellular dynamics at play that contribute to heterogeneity in CAF subsets may be essential for the design of novel therapies and improving clinical outcomes. Fortunately, recent advances in technologies such as microfluidics and bio-printing have made it possible to establish more advanced ex vivo models that will likely prove useful. In this review, we will present the different roles of stromal cells in pancreatic cancer, focusing on CAF origin as a source of heterogeneity, and the role this may play in therapy failure. We will discuss preclinical models that could be of benefit to the field and that may contribute to further clinical development.

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Single-cell analysis defines a pancreatic fibroblast lineage that supports anti-tumor immunity

Cited by 179 publications

References 92 publications

The Heterogeneity of the Tumor Microenvironment as Essential Determinant of Development, Progression and Therapy Response of Pancreatic Cancer

The Heterogeneity of the Tumor Microenvironment as Essential Determinant of Development, Progression and Therapy Response of Pancreatic Cancer

TGFβ Signaling in the Pancreatic Tumor Microenvironment

The Cellular Origins of Cancer-Associated Fibroblasts and Their Opposing Contributions to Pancreatic Cancer Growth

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