Type I collagen deletion in αSMA+ myofibroblasts augments immune suppression and accelerates progression of pancreatic cancer

Chen, Yang; Kim, Jiha; Yang, Stephen C.; Wang, Huamin; Wu, Chang Jiun; Sugimoto, Hikaru; LeBleu, Valerie S.; Kalluri, Raghu

doi:10.1016/j.ccell.2021.02.007

Cited by 339 publications

(331 citation statements)

References 101 publications

(114 reference statements)

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“…Importantly, targeting CAFs and associated responses by sonic hedgehog signaling inhibition has shown to reduce solid stress and IFP in tumor models, enhancing the activity of cytotoxic agents like taxol and 5′-fluorouracil (5′-FU) [ 146 , 154 , 155 , 156 ]. However, this strategy has failed in clinical trials and preclinical studies have shown that excessive depletion of CAFs might fuel tumor progression [ 157 , 158 , 159 ]. In addition to their role in solid stress accumulation, CAFs along with other stromal components promote the establishment of an immunosuppressive TME via the release of various immunosuppressive ligands such as TGF-β, CXCL12, IL-6, CXCL-1, G-SCF, and others which can impede intratumoral cytotoxic T cell infiltration and activity and enhance the recruitment of MDSCs, neutrophils and M2-like TAMs [ 160 ].…”

Section: Strategies To Improve Tumor Oxygenation and Therapeutic Efficacymentioning

confidence: 99%

The Role of Tumor Microenvironment in Cancer Metastasis: Molecular Mechanisms and Therapeutic Opportunities

Neophytou

Panagi

Stylianopoulos

et al. 2021

Cancers

212

106

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The tumor microenvironment (TME) regulates essential tumor survival and promotion functions. Interactions between the cellular and structural components of the TME allow cancer cells to become invasive and disseminate from the primary site to distant locations, through a complex and multistep metastatic cascade. Tumor-associated M2-type macrophages have growth-promoting and immunosuppressive functions; mesenchymal cells mass produce exosomes that increase the migratory ability of cancer cells; cancer associated fibroblasts (CAFs) reorganize the surrounding matrix creating migration-guiding tracks for cancer cells. In addition, the tumor extracellular matrix (ECM) exerts determinant roles in disease progression and cancer cell migration and regulates therapeutic responses. The hypoxic conditions generated at the primary tumor force cancer cells to genetically and/or epigenetically adapt in order to survive and metastasize. In the circulation, cancer cells encounter platelets, immune cells, and cytokines in the blood microenvironment that facilitate their survival and transit. This review discusses the roles of different cellular and structural tumor components in regulating the metastatic process, targeting approaches using small molecule inhibitors, nanoparticles, manipulated exosomes, and miRNAs to inhibit tumor invasion as well as current and future strategies to remodel the TME and enhance treatment efficacy to block the detrimental process of metastasis.

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Section: Strategies To Improve Tumor Oxygenation and Therapeutic Efficacymentioning

confidence: 99%

The Role of Tumor Microenvironment in Cancer Metastasis: Molecular Mechanisms and Therapeutic Opportunities

Neophytou

Panagi

Stylianopoulos

et al. 2021

Cancers

212

106

View full text Add to dashboard Cite

show abstract

“…As these results suggested that PSC-derived CAFs drive the establishment of a tumor-promoting desmoplastic milieu, we developed an ECM signature specific to or enriched among PSC-derived CAFs per our RNA-seq datasets. While collagen and bulk tumor stromal density associated with a better prognosis in PDAC (25, 27), this PSC-associated ECM signature associated with a worse prognosis among PDAC patients (Fig. 4I, Supplementary Table S1).…”

Section: Resultsmentioning

confidence: 97%

“…Genetic or pharmacologic ablation of CAFs during PDAC progression in mice—either targeting alpha-smooth muscle actin (α-SMA)-expressing CAFs (15) or Sonic Hedgehog-dependent CAFs (23, 24)—resulted in poorly differentiated tumors, and caused mice to succumb to disease faster than those with CAF-replete PDAC. In addition, stromal depletion of ECM component type I collagen significantly accelerated mortality in PDAC-bearing mice (25), and inhibition of collagen crosslinking by LOXL2 increased PDAC growth and reduced overall survival (26). Similarly, higher tumor stromal density, including cellular and acellular components of the stroma, associated with longer overall survival among PDAC patients (26, 27).…”

Section: Introductionmentioning

confidence: 99%

Mesenchymal Lineage Heterogeneity Underlies Non-Redundant Functions of Pancreatic Cancer-Associated Fibroblasts

Helms

Berry

Chaw

et al. 2021

Preprint

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Cancer-associated fibroblast (CAF) heterogeneity is increasingly appreciated, but the origins and functions of distinct CAF subtypes remain poorly understood. The abundant and transcriptionally diverse CAF population in pancreatic ductal adenocarcinoma (PDAC) is thought to arise from a common cell of origin, pancreatic stellate cells (PSCs), with diversification resulting from cytokine and growth factor gradients within the tumor microenvironment. Here we analyzed the differentiation and function of PSCs during tumor progression in vivo. Contrary to expectations, we found that PSCs give rise to a numerically minor subset of PDAC CAFs. Targeted ablation of PSC-derived CAFs within their host tissue revealed non-redundant functions for this defined CAF population in shaping the PDAC microenvironment, including production of specific components of the extracellular matrix. Together, these findings link stromal evolution from distinct cells of origin to transcriptional heterogeneity among PDAC CAFs, and demonstrate unique functions for CAFs of a defined cellular origin.Statement of significanceBy tracking and ablating a specific CAF population, we find that a numerically minor CAF subtype from a defined cell of origin plays unique roles in establishing the pancreatic tumor microenvironment. Together with prior studies, this work suggests that mesenchymal lineage heterogeneity as well as signaling gradients diversify PDAC CAFs.

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“…Recent studies showed that the matrix in the tumor stroma also participates in the immune response [ 97 ]. For example, high expression of Caveolin-1 (CAV1), a membrane-associated scaffold protein, enhances the secretion of Interleukin-6 (IL-6) and IL-8 in CAFs and promotes PC invasion, while the down-regulation of CAV1 slows down the proliferation of PC cells [ 98 ].…”

Section: The Role Of Fibrosis In Pcmentioning

confidence: 99%

Targeting Fibrosis: The Bridge That Connects Pancreatitis and Pancreatic Cancer

Huang

Iovanna

Santofimia‐Castaño

2021

IJMS

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Pancreatic fibrosis is caused by the excessive deposits of extracellular matrix (ECM) and collagen fibers during repeated necrosis to repair damaged pancreatic tissue. Pancreatic fibrosis is frequently present in chronic pancreatitis (CP) and pancreatic cancer (PC). Clinically, pancreatic fibrosis is a pathological feature of pancreatitis and pancreatic cancer. However, many new studies have found that pancreatic fibrosis is involved in the transformation from pancreatitis to pancreatic cancer. Thus, the role of fibrosis in the crosstalk between pancreatitis and pancreatic cancer is critical and still elusive; therefore, it deserves more attention. Here, we review the development of pancreatic fibrosis in inflammation and cancer, and we discuss the therapeutic strategies for alleviating pancreatic fibrosis. We further propose that cellular stress response might be a key driver that links fibrosis to cancer initiation and progression. Therefore, targeting stress proteins, such as nuclear protein 1 (NUPR1), could be an interesting strategy for pancreatic fibrosis and PC treatment.

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Type I collagen deletion in αSMA+ myofibroblasts augments immune suppression and accelerates progression of pancreatic cancer

Cited by 339 publications

References 101 publications

The Role of Tumor Microenvironment in Cancer Metastasis: Molecular Mechanisms and Therapeutic Opportunities

The Role of Tumor Microenvironment in Cancer Metastasis: Molecular Mechanisms and Therapeutic Opportunities

Mesenchymal Lineage Heterogeneity Underlies Non-Redundant Functions of Pancreatic Cancer-Associated Fibroblasts

Targeting Fibrosis: The Bridge That Connects Pancreatitis and Pancreatic Cancer

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