Abstract
Cancer-associated fibroblasts (CAFs) regulate diverse intratumoral biological programs and can promote or inhibit tumorigenesis, but those CAF populations that negatively impact the clinical outcome of lung cancer patients have not been fully elucidated. Because Thy-1 (CD90) marks CAFs that promote tumor cell invasion in a murine model of KrasG12D–driven lung adenocarcinoma (KrasLA1), here we postulated that human lung adenocarcinomas containing Thy-1+ CAFs have a worse prognosis. We first examined the location of Thy-1+ CAFs within human lung adenocarcinomas. Cells that co-express Thy-1 and α-smooth muscle actin (αSMA), a CAF marker, were located on the tumor periphery surrounding collectively invading tumor cells and in perivascular regions. To interrogate a human lung cancer database for the presence of Thy-1+ CAFs, we isolated Thy-1+ CAFs and normal lung fibroblasts (LFs) from the lungs of KrasLA1 mice and wild-type littermates, respectively, and performed global proteomic analysis on the murine CAFs and LFs, which identified 425 proteins that were differentially expressed. Used as a probe to identify Thy-1+ CAF-enriched tumors in a compendium of 1,586 lung adenocarcinomas, the presence of the 425-gene signature predicted a significantly shorter survival. Thus, Thy-1 marks a CAF population that adversely impacts clinical outcome in human lung cancer.
Highlights
In most tissues, fibroblasts are the primary stromal cells and are recognized by their spindle-shaped morphology and the absence of markers that define epithelial, immunologic, and other cell types
A Thy-1+ CD45− Epcam− population of Cancer-associated fibroblasts (CAFs) has been isolated from KrasLA1 mice, which develop multifocal lung adenocarcinomas owing to somatic activation of a latent KrasG12D allele[14]; these CAFs exhibit biochemical and morphological properties of myofibroblasts, secrete diverse growth factors and pro-angiogenic and immunosuppressive cytokines[15], and promote the invasive properties of lung adenocarcinoma cells derived from KrasLA1 mice in co-culture studies[15]
We postulated that the presence of Thy-1+ CAFs confers a worse prognosis in human lung adenocarcinoma
Summary
Fibroblasts are the primary stromal cells and are recognized by their spindle-shaped morphology and the absence of markers that define epithelial, immunologic, and other cell types. A Thy-1+ CD45− Epcam− population of CAFs has been isolated from KrasLA1 mice, which develop multifocal lung adenocarcinomas owing to somatic activation of a latent KrasG12D allele[14]; these CAFs exhibit biochemical and morphological properties of myofibroblasts, secrete diverse growth factors and pro-angiogenic and immunosuppressive cytokines[15], and promote the invasive properties of lung adenocarcinoma cells derived from KrasLA1 mice in co-culture studies[15]. These features of CAFs are not due to somatic activation of the latent KrasG12D allele, which is in germline configuration in CAFs15. These findings suggest that Thy-1 marks a CAF population that adversely impacts clinical outcome in human lung adenocarcinoma
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