Cancer-Associated Fibroblasts Regulate Kinase Activity in Mesothelioma Cell Lines via Paracrine Signaling and Thereby Dictate Cell Faith and Behavior

Abstract

Background: Malignant pleural mesothelioma (MPM) has an infaust prognosis due to resistance to systemic treatment with platin-analoga. MPM cells modulate the immune response to their benefit. They release proinflammatory cytokines, such as TGF-ß, awakening resting fibrocytes that switch their phenotype into activated fibroblasts. Signaling interactions between cancer cells and cancer-associated fibroblasts (CAFs) play an integral part in tumor progression. This study aimed to investigate the role CAFs play in MPM progression, analyzing the impact this complex, symbiotic interaction has on kinase-related cell signaling in vitro. Methods: We simulated paracrine signaling in vitro by treating MPM cell lines with conditioned medium (CM) from fibroblasts (FB) and vice versa. NCI-H2052, MSTO-211H, and NCI-H2452 cell lines representing the three mayor MPM subtypes, while embryonal myofibroblast cell lines, IMR-90 and MRC-5, provide a CAFs-like phenotype. Subsequently, differences in proliferation rates, migratory behavior, apoptosis, necrosis, and viability were used as covariates for data analysis. Kinase activity of treated samples and corresponding controls were then analyzed using the PamStation12 platform (PamGene); Results: Treatment with myofibroblast-derived CM revealed significant changes in phosphorylation patterns in MPM cell lines. The observed effect differs strongly between the analyzed MPM cell lines and depends on the origin of CM. Overall, a much stronger effect was observed using CM derived from IMR-90 than MRC-5. The phosphorylation changes mainly affected the MAPK signaling pathway.; Conclusions: The factors secreted by myofibroblasts in fibroblasts CM significantly influence the phosphorylation of kinases, mainly affecting the MAPK signaling cascade in tested MPM cell lines. Our in vitro results indicate promising therapeutic effects by the use of MEK or ERK inhibitors and might have synergistic effects in combination with cisplatin-based treatment, improving clinical outcomes for MPM patients.

Mesothelioma-associated fibroblasts enhance proliferation and migration of pleural mesothelioma cells via c-Met/PI3K and WNT signaling but do not protect against cisplatin

“…The same group also found in an immunohistochemistry study that CTGF expression in fibroblasts of PM specimens correlated with poor prognosis [ 43 ]. Recently, medium conditioned by cultures of the human lung fibroblasts MRC-5 and IMR-90 was shown to regulate the activity of multiple kinases in PM cells, especially those connected to the mitogen-activated protein kinase (MAPK) pathway [ 44 ]. To the best of our knowledge, this is the first study to characterize the transcript and protein expression patterns of patient-derived Meso-CAFs.…”

Mesothelioma-associated fibroblasts enhance proliferation and migration of pleural mesothelioma cells via c-Met/PI3K and WNT signaling but do not protect against cisplatin

“…The same group also found in an immunohistochemistry study that CTGF expression in broblasts of PM specimens correlated with poor prognosis [40]. Recently, medium conditioned by cultures of the human lung broblasts MRC-5 and IMR-90 was shown to regulate the activity of multiple kinases in PM cells, especially those connected to the mitogen-activated protein kinase (MAPK) pathway [41]. To the best of our knowledge, this is the rst study to characterize the transcript and protein expression patterns of patient-derived Meso-CAFs.…”

Damage-associated molecular patterns and sensing receptors based molecular subtypes in malignant pleural mesothelioma and implications for immunotherapy

“…The ATM pathway also regulates the suppression of anti-tumor immune cancer-associated fibroblasts (CAFs) differentiation (71). Advanced desmoplasia and stromal changes caused by CAFs have been identified as substantial factors in the progression of MPM (72). Accordingly, inhibition of ATM has the potential to overcome immune resistance in combination with ICIs in a minor subset of MPM patients of inflammatory DAMPs subtype.…”