Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer with a prominent extracellular matrix (ECM) deposition and poor prognosis. High levels of ECM proteins derived from tumour cells reduce the efficacy of conventional cancer treatment paradigms and contribute to tumour progression and metastasis. As abundant tumour-promoting cells in the ECM, cancer-associated fibroblasts (CAFs) are promising targets for novel anti-tumour interventions. Nonetheless, related clinical trials are hampered by the lack of specific markers and elusive differences between CAF subtypes. Here, we review the origins and functional diversity of CAFs and show how they create a tumour-promoting milieu, focusing on the crosstalk between CAFs, tumour cells, and immune cells in the tumour microenvironment. Furthermore, relevant clinical advances and potential therapeutic strategies relating to CAFs are discussed.
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Facts
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Subpopulations of CAFs in PDAC have distinct origins and functions, which can be either tumour-promoting or tumour-suppressing.
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Activated CAFs adapt to and co-evolve with pancreatic cancer cells, influencing PDAC behaviours via paracrine signalling.
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CAFs are orchestrators of the PDAC microenvironment and play a crucial role in hel** pancreatic cancer cells thrive in a hostile environment.
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A better understanding of metabolism in CAFs will benefit novel therapeutic paradigms, improving the prognosis of patients with PDAC.
Open questions
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In the PDAC microenvironment, heterogeneous CAFs serve different functions. How can we tell the difference between distinct subpopulations?
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CAFs are promising targets for anti-tumour interventions. Why do some therapies that target CAFs and ECM result in poorer outcomes?
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CAFs are metabolically linked to tumour cells in PDAC. Is this affecting CAFs’ immunomodulatory capacity? How can we use it to develop novel therapeutic strategies?
Introduction
Pancreatic cancer, one of the deadliest solid cancers, has remarkably poor prognosis, with a 5-year relative survival rate of only 9% [1]. Pancreatic ductal adenocarcinoma (PDAC), its most common subtype, accounts for approximately 85% of pancreatic malignancies [2]. Despite numerous studies on the disease and the development of new treatment options, early diagnosis and comprehensive treatment for PDAC remain difficult. Most patients are diagnosed at an advanced stage, and the majority of cases are evaluated as unresectable, with only palliative treatment options. Standard chemotherapy regimens for PDAC patients include nab-paclitaxel plus gemcitabine combination therapy or FOLFIRINOX (5-fluorouracil, leucovorin, irinotecan, oxaliplatin), but survival rates have not improved significantly [3]. Furthermore, due to the complex tumour microenvironment (TME), pancreatic cancer exhibits significant resistance to radiotherapy [4]. In contrast, a small subset of PDAC patients with resectable tumours had improved survival after receiving modified FOLFIRINOX (excluding 5-fluorouracil) [5, 6]. However, some patients still have to face a high risk of postoperative recurrence [6]. Hence, it is critical to find an effective treatment as soon as possible.
PDAC typically develops a dense fibrotic stroma with an abundance of extracellular matrix (ECM) due to the inflammation-induced desmoplastic reaction [7]. Cancer-associated fibroblasts (CAFs) are known to be the most important cellular component of the ECM [8]. The stroma is composed of various ECM-related proteins derived from CAFs, including collagen and hyaluronan (HA), and has been linked to intra-tumoural pressure and vasculature [9, 10]. Aside from CAF-mediated TME remodelling, numerous studies have shown that CAFs secrete various paracrine factors that promote tumour invasion, metastasis, and chemoresistance [11]. In the TME, a complex web of signalling connects tumour cells and other cellular components, such as suppressed immune cells like regulatory T cells (T-regs), myeloid-derived suppressor cells (MDSCs), and tumour-associated macrophages (TAMs) [12,13,14]. CAFs are involved in negative immune regulation, inhibiting the cytotoxic activity of CD8+ cells in PDAC, resulting in poor immunotherapy outcomes [15]. Although CAFs have potent tumour-promoting effects, tumour suppressor functions for some CAF subsets also have been reported [16, 17]. It has been demonstrated that CAFs are made up of heterogeneous subtypes that either promote or inhibit tumour growth using single-cell RNA sequencing (scRNA-seq) technology [18, 19]. Although many studies consider CAFs a potential therapeutic target, the lack of highly specific CAF markers makes future research difficult [20]. This review summarises current knowledge about the origins and subtypes of CAFs in PDAC focusing on their functions, such as tumour microenvironment remodelling, metabolic reprogramming, and tumour immunity regulation. Finally, we will go over therapeutic strategies that target CAFs to hasten the transition from bench to bedside.
Sources and subpopulations of CAFs in PDAC
Origins of CAFs
It has long been recognised that CAFs represent a heterogeneous population in a variety of malignant tumours [21, 22]. In PDAC, stromal CAFs are often derived from all kinds of cell types, including pancreatic stellate cells (PSCs), tissue-resident fibroblasts, and tumour-infiltrating mesenchymal stem cells (MSCs) [23]. In previous research, PSCs were believed to be the primary progenitor cells of CAFs in PDAC [24, 25]. Approximately 4–7% of typical pancreatic cells are quiescent PSCs, which operate to store vitamin A [26, 27]. Once activated by cytokines, such as transforming growth factor-β (TGF-β), interleukin-6 (IL-6), platelet-derived growth factor (PDGF), and Sonic hedgehog (Shh) [28,29,30,31], PSCs lose vitamin A and start expressing α-Smooth Muscle Actin (α-SMA), which is considered a characteristic CAFs marker [32,33,34]. Unexpectedly, a recent study tracing specific CAF populations in murine models revealed that PSC-derived CAFs represent only a small portion of all CAFs [35]. In addition, it has been shown that adipocytes, pericytes, bone marrow (BM)-derived macrophages, and endothelial cells can differentiate into CAFs and be recruited to the tumour site [36, 37]. Waghray et al. identified cancer-associated MSCs (CA-MSCs) as a specific subpopulation of CAFs [38]. CA-MSCs secrete the granulocytic-macrophage colony-stimulating factor (GM-CSF) exclusively, thereby promoting the progression of PDAC [39, 40]. Moreover, it was discovered that CA-MSCs regulate macrophage polarisation in a tumour-promoting manner. As has been reported recently, BM-derived macrophages are recruited to the pancreas and partially converted into CAF-like cells [41]. CAFs can also be transdifferentiated from non-fibroblastic lineages, such as epithelial and endothelial cells, adipocytes, and pericytes (Fig. 1) [23, 42,43,83, 84].
Restricting tumour-infiltrated immune cells
In pancreatic tumours, CAFs inhibit immune cell infiltration by generating a dense fibrotic stroma, as has been extensively discussed, but they can also directly modulate the anti-tumour activity of a variety of immune cells. Dendritic cells (DCs), TAMs, MDSCs, T-regs, and cytotoxic T cells make up the PDAC immune microenvironment [85, 86]. The majority of resident immune cells are educated to be immunosuppressive, making PDAC one of the most immunosuppressive tumours [16]. Pancreatic CAFs secrete chemokines, cytokines, and growth factors to recruit and regulate these immunosuppressive cells [87]. Thus, TAMs, MDSCs, and T-regs have been proven to suppress anti-tumoural responses and enhance tumour growth [88, 89]. Furthermore, the dense stroma prevents CD8+ T cells from killing tumour cells, resulting in a poor immunotherapy outcome for PDAC [90]. PSCs generate MDSC-promoting cytokines such as IL-6, VEGF, M-CSF, and chemokines (SDF-1, MCP-1) [91, 92]. These factors promote the differentiation of peripheral blood mononuclear cells into MDSCs, then promote tumour progression by suppressing T-cell proliferation and stimulating cancer cell vascularisation and metastasis [92]. Furthermore, a study has shown that CAF-derived LIF also plays an important role in the differentiation of MDSCs [93]. In addition, some activated fibroblasts express fibroblast activation protein-α (FAPα), which cleaves type I collagen (Col 1) and increases macrophage adhesion [94]. These findings suggest that CAFs promote MDSCs differentiation, leading to an immunosuppressive microenvironment.
Tumour cells can be recognised and killed by infiltrating CD8+ T cells and evade immune surveillance by inducing T-cell exhaustion [87]. CAFs contribute to immune escape by releasing suppressive cytokines and chemokines, such as IL-6, IL-1β, CXCL1, CXCL2, and CXCL12, and expressing immune checkpoint ligands [95]. Furthermore, as the primary producers of ECM, activated CAFs promote fibrosis, which compresses intra-tumoural vessels and impedes the infiltration of tumour-reactive immune cells [96]. Immune checkpoint ligands, such as CTL-associated antigen 4 (CTLA-4) and programmed death-ligand 1 (PD-L1), bind to effector T cells and contribute to their dysfunction [97, 98]. Gorchs and colleagues demonstrated that Prostaglandin E2 (PGE2) released by pancreatic CAFs inhibits T-cell proliferation and contributes to the upregulation of immune checkpoint markers such as CTLA-4 and PD-1 on activated T cells, resulting in impaired immune function [99]. Another study found that CXCL12, which FAP+ CAFs secrete, inhibits the accumulation of cytotoxic T cells in the vicinity of the tumour and may direct tumour immune evasion in a human PDAC model [100]. CAFs enhance the formation of the immunosuppressive microenvironment in PDAC by regulating immune cell activity. However, it is worth noting that different subtypes of CAFs may play distinct roles in this process. Tumour-promoting inflammatory factors, including IL-6, LIF, and CXCL8, are mainly secreted by iCAFs but not myCAFs [50]. In addition, the deletion of Col 1 in α-SMA+ myCAFs leads to CXCL5 upregulation in cancer cells, which is associated with recruitment of MDSCs and suppression of CD8+ T cells, suggesting that myCAFs slow tumour progression in PDAC [101]. Therefore, further investigations are required to understand better the functional heterogeneity of CAFs in the TME of pancreatic cancer.
Reprograming tumour metabolism
In PDAC, the fibrotic stroma limits the availability of nutrients and oxygen [102]. In order to survive, pancreatic cancer cells rewire the metabolic network, switching from oxidative phosphorylation (OXPHOS) to aerobic glycolysis, which is known as the Warburg Effect. Surprisingly, PDAC could hijack nearby CAFs and provide them with energy and nutrients. The ‘Reverse Warburg Effect’ occurs when CAFs are induced to undergo metabolic reprogramming similar to aerobic glycolysis [103]. CAFs secrete energy-rich metabolites such as lactate and pyruvate, which are then taken up by cancer cells and used to fuel OXPHOS, promoting efficient energy production [104, 105]. By interacting with CAFs and other ECM components in the TME, neoplastic cells represent an intricate reprogramming of metabolism [106]. Moreover, CAFs also stimulate glycolytic metabolism via paracrine hepatocyte growth factor (HGF) [107]. Furthermore, through autophagy, CAFs can provide alanine as an alternative carbon source to maintain tumour metabolism and growth [108]. As previously demonstrated, alanine may compete with glucose and glutamine to support OXPHOS and thus nonessential amino acid and lipid biosynthesis in PDAC [109]. Beyond the direct supply of metabolites, CAFs also nourish tumours by producing nutrient-rich ECM. For example, extracellular collagen can be taken up by malignant cells and serve as a source of proline [110]. Recently, Kim et al. found that hyaluronic acid in the ECM can also serve as a nutrient fuel for PDAC metabolism [111]. In addition, by tracking carbon-13-labeled metabolites, Zhao et al. found that CAF-derived exosomes can be taken up by tumour cells in a macropinocytosis-like manner and provide carbon sources such as amino acids and lipids [112]. Collectively, CAFs play a crucial role in hel** tumours thrive in a hostile environment (Fig. 3).
Clinical trials related to CAFs
Lumakras (sotorasib), a novel KRAS G12C inhibitor, is being tested in clinical trials and has shown promising results in patients with advanced pancreatic cancer [113]. It is estimated that almost 90% of pancreatic cancer patients have KRAS mutations. However, KRAS G12C accounts for only 1–2% of these mutations, implying that it will benefit only a small percentage of patients with PDAC [114]. As previously stated, CAFs have many tumour-promoting functions in the PDAC tumour microenvironment, including inhibiting drug delivery, metabolic reprogramming, and immunosuppression, making them a promising target for cancer intervention. While our understanding of CAFs is still develo**, several preclinical studies and clinical trials have been published. However, given the origin and function heterogeneity of CAFs, develo** clinical interventions targeting CAFs still faces numerous obstacles and challenges (Fig. 4).
Targeting ECM depletion
Since the massive deposition of ECM forms a physical barrier that inhibits chemotherapeutic drug delivery and increases radiotherapy resistance, it is hypothesised that targeting ECM depletion will improve cancer treatment [115]. Among the various components of the ECM, HA and collagens have received the most attention [16]. In preclinical models, however, the absence of Col 1 results in the upregulation of CXCL5 in tumour cells and the recruitment of MDSCs [116]. Losartan was used to target HA, leading to decreased ECM deposition in an orthotopic tumour, which improved patient survival [117]. According to another antifibrotic therapy, the combination of pegvorhyaluronidase-α (PEGPH20) and gemcitabine inhibited tumour desmoplastic reactions and improved overall survival in KPC (Pdx1-Cre;lox-stop-lox-KrasG12D/+;lox-stop-lox-Trp53R172H/+) mice [118]. However, Ramanathan evaluated the activity of PEGPH20 with modified FOLFIRINOX (mFOLFIRINOX) in patients with metastatic pancreatic cancer and found that this combination heightened toxicity and resulted in a shorter treatment duration when compared to mFOLFIRINOX alone [119]. A randomised phase III clinical trial evaluated the efficacy and safety of PEGPH20 with nab-paclitaxel/gemcitabine (AG) in patients with metastatic pancreatic cancer. The combination did not improve OS or PFS [120]; it seems insufficient to target the ECM alone because of poor clinical outcomes, and the dynamic crosstalk between tumour and stromal cells should be considered. In a preclinical research, FAP-specific chimeric antigen receptor T (CAR-T) cells were designed to deplete FAP+ CAFs, showing anti-tumour function without significant toxicity [121]. Nevertheless, FAP+ cells originating from normal tissues and organs also exhibit highly similar transcriptomic profiles, suggesting that this therapy might lead to the killing of normal cells [122]. Moreover, the inhibition of lysyl oxidase (LOX) by a monoclonal antibody simtuzumab (GS-6624) is also utilised to curb collagen cross-linking and target the protumourigenic stroma [123]. However, simtuzumab in combination with gemcitabine did not achieve significant efficacy in the treatment of pancreatic cancer in adults in a phase II clinical trial [124]. Overall, matrix-targeted agents improve patient outcomes more complex than physical ablation of specific ECM components, so matrix-targeted therapeutic strategies still need further investigation [125].
Normalisation of activated CAFs
Some researchers are more interested in reprogramming activated CAFs into a dormant state than in CAFs ablation [53]. Since vitamin A deficiency is linked to quiescent fibroblasts activation, restoring retinol levels in PSCs with the all-trans retinoic acid (ATRA) may reverse the state of activated CAFs [126]. Froeling et al. found that ARTA induces quiescence of stromal fibroblasts, with reduced expansion and increased apoptosis of PDAC cells in murine models. When ATRA is combined with gemcitabine, tumour proliferation and invasion decrease, while apoptosis increases compared to the agent alone [127]. Furthermore, calcipotriol, a vitamin analogue, is administered with gemcitabine, resulting in induced stromal remodelling, increased intra-tumoural gemcitabine accumulation, decreased tumour volume, and a 57% increase in survival in KPC mice compared to chemotherapy alone [128]. However, it has been reported that calcipotriol can also up-regulate PD-L1 on cancer cells thereby impairing the anti-tumour function of cytotoxic T cells [129]. Furthermore, some potential mechanisms that aid in the normalisation of CAFs are being investigated. Minnelide is a triptolide analogue with potent bioactivities against a variety of cancers. Dauer et al. discovered TGF-β signalling deregulation in CAFs after Minnelide treatment, resulting in a significant transition from an activated to a quiescent state [130]. Moreover, Lipoxin A4 (LXA4), an endogenous bioactive lipid, inhibits the differentiation of PSCs into CAF-like myofibroblasts and the associated tumour-promoting effects [131]. Thus, efforts to normalise tumour-promoting CAFs or reverse their activated state may open up new avenues for develo** novel anti-tumour therapies. In contrast to the fact that PSCs give rise to only a minor subpopulation of CAFs in human PDAC, the majority of related studies have been based on the misconception that PSCs are the major precursors of CAFs [35]. It reminds frontline researchers to focus more on the heterogeneity and diversity of CAFs in primary human tumours. In addition, converting iCAF to myCAF appears to be a promising strategy for ameliorating the immunosuppressive microenvironment. The formation of iCAFs is dominated by IL-1/Jak-Stat signalling, and a Phase I clinical trial of anakinra (IL-1R antagonist) in combination with chemotherapy is currently underway [70, 132].
Targeting CAF-related signalling
Prior data have highlighted the vital roles of CAF-related signalling pathways in the various stages of pancreatic cancer progression [113, 133]. Integrins have been investigated as pharmaceutical targets for reducing ECM. They are extensively expressed by malignant and stromal cells at focal adhesion. It was reported that inhibiting integrin could significantly slow tumour progression [134]. Monoclonal antibodies that targets integrin, such as Volociximab, has shown therapeutic efficacy in clinical trials to treat pancreatic cancer patients [135]. Furthermore, Jiang et al. discovered that the focal adhesion kinase (FAK) inhibitor VS-4718 may reduce ECM remodelling, while increasing sensitivity to chemotherapy and immunotherapy [136]. Feig and colleagues discovered that FAP+ CAFs secreted CXCL12, leading to PDAC immunosuppression [100]. Garg et al. discovered that CXCL12 inhibited cytotoxic T cell infiltration. Blocking CXCL12’s effect on PDAC cells may improve anti-tumour immunity [137]. AMD3100 is an inhibitor of CXCR4 (receptor of CXCL12), and it is reported to promote CD8+ T cells infiltration in combination with PD-L1 blockade [100]. Furthermore, TGF-β has emerged as a promising target for the treatment of pancreatic cancer [138]. However, in previous preclinical study, TGF-β blockade increased tumour cell proliferation and accelerated both early and later disease stages [139]. Galunisertib was the first oral TGF-β receptor inhibitor and improved prognosis in advanced PDAC patients in combination with gemcitabine or durvalumab [140, 141]. Notably, it was discovered that TGF-β receptor 2 blockade reduced IL-6 from CAFs, resulting in a reduction of STAT3 activation in cancer cells and improve the anti-tumour immune response [142]. Lan et al. designed a bifunctional protein called M7824, which inhibits tumourigenesis by blocking both PD-L1 and TGF-β signalling. In mouse models, it suppressed tumour growth and metastasis more effectively than treatment with either an anti-PD-L1 antibody or TGF-β trap alone [143]. More research should be done to explore if inhibiting TGF-β signalling in combination with immunotherapy or chemotherapy can improve the prognosis of PDAC, and any side effects from the combination also need to be avoided. In addition, Grauel et al. found that neutralization of TGF-β in vivo led to a dramatic disruption in myCAF activity while boosting the formation of interferon-licensed CAF subsets [144]. It appears that targeting activating signals also contributes to ECM remodelling and is beneficial for enhancing antitumour immunity [145, 146]. However, a better understanding of the role of the ECM in antitumour immunity is required before reliable immunotherapy can be established [147]. Recently, it is found that specific targeting of CAFs-derived HIF-2α can also inhibit cancer cell proliferation and alleviate tumour immunosuppression, providing a new therapeutic target for PDAC [148]. The current therapies involving CAF-targeting agents in pancreatic cancer are summarised in Table 3.
Conclusions and perspectives
CAFs are promising treatment targets because they are the most dynamic and complex components in the pancreatic stroma. On the contrary, CAFs are very heterogeneous, which necessitates further identification and characterisation. Patients with pancreatic cancer may benefit from more specific and personalised therapies if we better understand the diversity of CAFs. CAFs contribute to several features of PDAC, including the deposition of ECM, metabolic support for malignant cells, and immunosuppression. Francescone et al. characterised the functions of Netrin G1 (NetG1) on CAFs in PDAC [149]. NetG1+ CAFs not only contribute to immunosuppressive TME, but also allow tumour cells to overcome nutrient deprivation by providing glutamine and glutamate. Specific blockade of NetG1 with a monoclonal antibody inhibits tumour growth and alleviate immunosuppression in mouse models, which also suggests a novel potential target. Furthermore, Wang et al. discovered a new subtype of CAFs with enhanced metabolic activity (meCAF) in PDAC with low desmoplasia, which are characterised as undergoing highly active glycolysis and metabolically coupled with adjacent cancer cells [150]. In addition, PDAC patients with an abundance of meCAFs responded dramatically better to immunotherapy, though more direct evidence is required to further confirm their immunomodulatory function. Francescone et al. demonstrated that inhibiting metabolic-related proteins in CAFs altered their immunosuppressive capacity, linking cell metabolism and immunomodulatory function [149]. As the metabolic link between different subsets of CAFs and tumour cells and immune cells remains elusive, most of the related studies are still in the preclinical stage and there are no reliable clinical translational research results. The role of metabolism-targeted therapy in CAFs should also be emphasised in future research, including the effects on the tumour cells and the modulation of the immune microenvironment. In conclusion, we believe a better understanding of metabolism in CAFs will benefit novel therapeutic paradigms, improving the prognosis of patients with PDAC.
Data availability
Data openly available in a public repository (https://clinicaltrials.gov/).
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This work was supported by the National Nature Science Foundation of China (NO. 11905264, HZ), the Youth Fund of the First Hospital of Lanzhou University (NO. ldyyyn2020-64, YR). All the figures were created by BioRender.
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HZ conceived and designed the review; TZ and YR were responsible for the retrieval and collation of relevant literature; PY and JW modified and polished the manuscript; TZ and HZ wrote the original draft.
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Zhang, T., Ren, Y., Yang, P. et al. Cancer-associated fibroblasts in pancreatic ductal adenocarcinoma. Cell Death Dis 13, 897 (2022). https://doi.org/10.1038/s41419-022-05351-1
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DOI: https://doi.org/10.1038/s41419-022-05351-1
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