Abstract 4404: CSF-1R signaling drives mesothelioma stemness and chemoresistance
Authors: Cioce Mario , Canino Claudia , Goparaju Chandra , Yang Haining , Carbone Michele , Pass Harvey I. 
Published: May 2015

Clinical management of Malignant Pleural Mesothelioma (MPM) is very challenging because of the uncommon resistance of the tumor to chemotherapy. We started from the observation that 7/7 mesothelioma cell lines tested expressed both the Colony Stimulating Factor Receptor-1 and its -ligands CSF-1 and IL-34, a signaling module mainly characterized in hematopoietic cell subpopulations. Pemetrexed and cisplatin treatment did not affect the number of mesothelioma CSF1R-expressing cells. Additionally, interference with CSF1R expression or function significantly abrogated the resistance of these cells to pemetrexed, suggesting the involvement of CSF-1R signaling in mediating chemoresistance of mesothelioma. This prompted us to isolate and characterize the CSF-1Rpos cells and we found that the purified cells expressed a complex repertoire of pluripotency markers, EMT factors and chemoresistance genes. The functions of the CSF-1R expressing MPM cells relied on the autocrine production of CSF-1 and IL-34, whose downregulation affected the viability of the purified cells. We identified AKT, NFkB and STAT3 activation as distinct features of the CSF-1Rpos cells. We showed that all three pathways contributed to the survival of the CSF1Rpos cells, with AKT exerting the most relevant effects. The forced activation of CSF-1R in untransformed mesothelial cells was sufficient to confer clonogenicity and resistance to pemetrexed, typical feature of transformed mesothelial cells. Furthermore, this induced a gene expression profile very similar to that observed in the FACS sorted CSF-1Rpos cells, suggesting a causal relationship between CSF-1R activation and cell transformation. Active AKT signaling contributed to increased levels of nuclear β-catenin in the CSF-1R expressing cells. Inhibition of AKT reduced the transcriptional activity of β-catenin dependent reporters and sensitized the CSF-1Rpos cells to pemetrexed-induced senescence, thereby reversing the resistance of the CSF1Rpos cells to pemetrexed. This correlated with downregulation of c-MYC, a functional CSF-1R target, and upregulation of p21. Finally, we recapitulated the main findings in primary mesothelioma cultures, which exhibited long-term surviving, chemoresistant CSF-1Rpos cells of mesothelial nature and sensitive to CSF-1R inhibition. This work expands what is known on the non-macrophage functions of CSF-1R and its role in solid tumors, suggests that CSF-1R signaling may have a critical pathogenic role in malignant pleural mesothelioma and therefore may represent a promising target for therapeutic intervention.

Citation Format: Mario Cioce, Claudia Canino, Chandra Goparaju, Haining Yang, Michele Carbone, Harvey I. Pass. CSF-1R signaling drives mesothelioma stemness and chemoresistance. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4404. doi:10.1158/1538-7445.AM2014-4404