Key Takeaways & Executive Findings
- •• • PDGFC expression is significantly higher in CAFs than in nontumor fibroblasts (NFs), and elevated PDGFC correlates with poor prognosis in LUAD patients (p < 0.05). This establishes PDGFC as a prognostic biomarker and a candidate for targeted intervention in stroma-rich tumors. • • CAF-derived PDGFC promotes EMT and MMP2 expression in cancer cells via the PDGFRA-MAPK/ERK pathway. MMP2, a PDGFRA-related gene, is associated with poor prognosis, indicating that PDGFC inhibition could reduce extracellular matrix degradation and metastatic dissemination. • • PDGFC induces increased PDGFRA expression in both tumor cells and fibroblasts, creating a reciprocally positive feedback loop that accelerates fibrotic TME remodeling and malignant progression. This self-amplifying circuit represents a therapeutic vulnerability; interrupting PDGFC-PDGFRA signaling may dismantle the fibrotic barrier and enhance drug penetration. • • PDGFC facilitates immunosuppression by promoting infiltration and polarization of Treg cells, M2 macrophages, and N2 neutrophils, while restraining NK cell infiltration. Immunoinhibitors TGFB1, CSF1R, PD-L1, PD-L2, KDR, IL10RB, and HAVCR2 may synergize with PDGFC, suggesting combination strategies to overcome immunotherapy resistance in LUAD.
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Abstract
Lung adenocarcinoma (LUAD) remains a leading cause of cancer-related mortality, with late-stage 5-year survival rates below 50%. Cancer-associated fibroblasts (CAFs) within the tumor microenvironment (TME) drive progression, yet the molecular mediators of CAF-tumor crosstalk are incompletely defined. This study identifies platelet-derived growth factor C (PDGFC) as a critical CAF-secreted factor that promotes epithelial-mesenchymal transition (EMT) and immunosuppression in LUAD. Analysis of patient specimens revealed elevated PDGFC expression in CAFs relative to nontumor tissue fibroblasts (NFs), and high PDGFC levels correlated with poor prognosis. Mechanistically, CAF-derived PDGFC activates the PDGF receptor A (PDGFRA)-mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathway in cancer cells, inducing EMT and matrix metalloproteinase 2 (MMP2) expression. PDGFC also stimulates PDGFRA expression in both tumor cells and fibroblasts, establishing a reciprocal positive feedback loop that accelerates fibrotic TME remodeling and malignant progression. Immunologically, PDGFC promotes infiltration and polarization of immunosuppressive cell populations, including CD4+ Treg cells, M2 macrophages, and N2 neutrophils, while restraining immunocompetent NK cells. Immunoinhibitors TGFB1, CSF1R, PD-L1, PD-L2, KDR, IL10RB, and HAVCR2 may synergize with PDGFC in modulating immunosuppression. These findings position PDGFC as a diagnostic indicator and potential immunotherapy target for LUAD, offering a novel TME-targeted therapeutic strategy.
1. Introduction
Lung adenocarcinoma (LUAD) accounts for a substantial proportion of lung cancer cases, and despite advances in comprehensive treatments, the 5-year survival rate for late-stage patients remains below 50%. The tumor microenvironment (TME) plays a pivotal role in LUAD progression, with cancer-associated fibroblasts (CAFs) emerging as key architects of TME remodeling. CAFs exhibit heterogeneous origins and functions, and their secreted factors drive tumor proliferation, invasion, and immune evasion. Platelet-derived growth factors (PDGFs) and their receptors are implicated in oncogenesis and drug resistance, but the specific contribution of PDGFC, a member of the PDGF family, to LUAD pathology has remained undefined. Existing therapeutic approaches targeting the TME have largely failed due to incomplete understanding of the molecular crosstalk between CAFs and cancer cells, underscoring the need to identify actionable mediators.
This study addresses the bottleneck by elucidating the mechanisms through which CAF-derived PDGFC promotes LUAD progression. We demonstrate that PDGFC is overexpressed in CAFs relative to nontumor fibroblasts and correlates with poor prognosis. PDGFC activates the PDGFRA-MAPK/ERK pathway in cancer cells, inducing epithelial-mesenchymal transition (EMT) and matrix metalloproteinase 2 (MMP2) expression. Furthermore, PDGFC establishes a reciprocal positive feedback loop by upregulating PDGFRA in both tumor cells and fibroblasts, accelerating fibrotic TME remodeling. Immunologically, PDGFC drives immunosuppression by promoting Treg, M2 macrophage, and N2 neutrophil infiltration while suppressing NK cells. These findings provide a novel TME-targeted strategy for LUAD treatment, with PDGFC as a potential diagnostic and immunotherapeutic target.
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CUI Meimei, DING Xiaodi, JIANG Yu, ZHANG Liying, CAO Wangkai, WANG Yongming, SHENG Zhimei, SUN Wei, GUO Ai, GU Lihui, ZHANG Xiurong, DUAN Wanli, SHI Lihong, ZHANG Baogang (2025). PDGFC Secreted by Cancer-Associated Fibroblasts Promotes Epithelial-Mesenchymal Transition and Immunosuppression in Lung Adenocarcinoma. Acta Biochimica et Biophysica Sinica. https://doi.org/10.3724/abbs.2025042
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Frequently Asked Questions
What is the specific molecular mechanism by which CAF-derived PDGFC promotes EMT in LUAD cells?
CAF-derived PDGFC binds to PDGFRA on cancer cells, activating the MAPK/ERK signaling pathway. This activation induces EMT and upregulates MMP2 expression. MMP2 degrades the extracellular matrix, facilitating invasion and migration. The PDGFRA-MAPK/ERK axis is critical; inhibition of this pathway abrogates PDGFC-induced EMT and MMP2 production, as demonstrated in our in vitro and in vivo experiments.
How does PDGFC contribute to immunosuppression in the tumor microenvironment?
PDGFC promotes the infiltration and polarization of immunosuppressive cell populations: CD4+ Treg cells, M2 macrophages, and N2 neutrophils. Concurrently, it restrains the infiltration of immunocompetent NK cells. This shift creates an immunosuppressive TME that supports tumor progression. Additionally, PDGFC expression positively correlates with immunoinhibitors such as TGFB1, CSF1R, PD-L1, PD-L2, KDR, IL10RB, and HAVCR2, suggesting synergistic mechanisms that blunt anti-tumor immunity.
What is the clinical significance of the reciprocal positive feedback loop between PDGFC and PDGFRA?
PDGFC induces increased PDGFRA expression in both tumor cells and fibroblasts, establishing a self-amplifying loop that accelerates fibrotic TME remodeling and malignant progression. This feedback loop creates a barrier to drug delivery and promotes resistance to therapy. Targeting PDGFC or PDGFRA could disrupt this cycle, reduce fibrosis, and enhance the efficacy of immunotherapies or chemotherapeutics. The correlation of PDGFC with poor prognosis underscores its potential as a therapeutic target.
What are the limitations of this study regarding CAF heterogeneity?
The study did not dissect the pleiotropic effects of different CAF subsets, which arise from heterogeneous origins and spatial distributions. CAF heterogeneity may influence the net effect of PDGFC on tumor progression and immune modulation. Future research should characterize CAF subpopulations and their specific contributions to PDGFC-mediated effects to refine therapeutic targeting and avoid unintended consequences.
What are the potential therapeutic implications of targeting PDGFC in LUAD?
PDGFC serves as both a diagnostic indicator and a potential immunotherapy target. Inhibiting PDGFC could reduce EMT, MMP2-mediated matrix degradation, and immunosuppression, thereby sensitizing tumors to immune checkpoint inhibitors. Combination strategies targeting PDGFC alongside immunoinhibitors like PD-L1 or TGFB1 may yield synergistic effects. However, clinical validation is required to determine efficacy, safety, and patient selection criteria.
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