Cancer-associated fibroblast activation predicts progression, metastasis, and prognosis of cutaneous squamous cell carcinoma

Cutaneous squamous cell carcinoma (cSCC) is the most common metastatic skin cancer and the metastatic disease is associated with poor prognosis. Cancer-associated fibroblasts (CAFs) promote progression of cancer, but their role in cSCC is largely unknown. We examined the potential of CAF markers in the assessment of metastasis risk and prognosis of primary cSCC. We utilized multiplexed fluorescence immunohistochemistry for profiling CAF landscape in metastatic and non-metastatic primary human cSCCs, in metastases, and in premalignant epidermal lesions. Quantitative high-resolution image analysis was performed with two separate panels of antibodies for CAF markers and results were correlated with clinical and histopathological parameters including disease-specific mortality. Increased stromal expression of fibroblast activation protein (FAP), alpha-smooth muscle actin, and secreted protein acidic and rich in cysteine (SPARC) were associated with progression to invasive cSCC. Elevation of FAP and platelet-derived growth factor receptor-beta (PDGFR beta) expression was associated with metastasis risk of primary cSCCs. High expression of PDGFR beta and periostin correlated with poor prognosis. Multimarker combination defined CAF subset, PDGFR alpha-/PDGFR beta+/FAP+, was associated with invasion and metastasis, and independently predicted poor disease-specific survival. These results identify high PDGFR beta expression alone and multimarker combination PDGFR alpha-/PDGFR beta+/FAP+ by CAFs as potential biomarkers for risk of metastasis and poor prognosis. Assessing metastatic risk and prognosis of cutaneous squamous cell carcinoma (cSCC) is hindered by a lack of biomarkers. Cancer-associated fibroblasts (CAFs), however, may yield markers relevant to prognosis, owing to their possible association with cSCC progression. Here, CAFs were investigated for associations with cSCC metastasis and prognosis using multiplexed fluorescence immunohistochemistry. The proportion of CAFs expressing platelet-derived growth factor receptor-beta (PDGFR beta) was elevated in metastatic cSCC. Likewise, metastasis and poor prognosis were associated with CAF PDGFR beta positivity, PDGFR alpha negativity, and fibroblast activation protein (FAP) expression. The findings offer novel insight into the role of CAFs in cSCC progression and metastasis. image