Abstract
Pancreatic ductal adenocarcinoma (PDA) shows a rich stroma where cancer-associated fibroblasts (CAFs) represent the major cell type. CAFs are master secretors of proteins with pro-tumor features. CAF targeting remains a promising challenge for PDA, a devastating disease where treatments focusing on cancer cells have failed. We previously introduced a novel pharmacological CAF-targeting approach using the somatostatin analog SOM230 (pasireotide) that inhibits protein synthesis in CAFs, and subsequent chemoprotective features of CAF secretome. Using primary cultures of CAF isolated from human PDA resections, we here report that CAF secretome stimulates in vitro cancer cell survival, migration and invasive features, that are abolished when CAFs are treated with SOM230. Mechanistically, SOM230 inhibitory effect on CAFs depends on the somatostatin receptor subtype sst1 expressed in CAFs but not in non-activated pancreatic fibroblasts, and on protein synthesis shutdown through eiF4E-Binding Protein-1 (4E-BP1) expression decrease. We identify interleukin-6 as a SOM230-inhibited CAF-secreted effector, which stimulates cancer cell features through phosphoinositide 3-kinase activation. In vivo, mice orthotopically co-xenografted with the human pancreatic cancer MiaPaCa-2 cells and CAFs develop pancreatic tumors, on which SOM230 treatment does not inhibit growth but abrogates metastasis. Consistently, CAF secretome stimulates epithelial-to-mesenchymal transition in cancer cells, which is reversed upon CAF treatment with SOM230. Our results highlight a novel promising anti-metastatic potential for SOM230 indirectly targeting pancreatic cancer cell invasion through pharmacological inhibition of stromal CAFs.
Highlights
Tumorigenesis has classically been viewed as a largely cell-autonomous process involving genetically transformed cancer cells, the importance of stromal cell types populating the neoplastic microenvironment is well accepted and needs to be taken into account for future therapeutic strategies [1, 2]
High protein synthesis in cancerassociated fibroblasts (CAFs) is responsible for the secretion of growth-promoting factors – phenotype reversion with the somatostatin analog SOM230
Immortalization of a CAF primary culture through overexpression of hTERT reverted its growthpromoting effect on cancer cells, in correlation with the loss of expression of αSMA (Supplementary Figure 1A and 1B), confirming the StellaTUM recommendation to work with primary cultures of CAF only [18]
Summary
Tumorigenesis has classically been viewed as a largely cell-autonomous process involving genetically transformed cancer cells, the importance of stromal cell types populating the neoplastic microenvironment is well accepted and needs to be taken into account for future therapeutic strategies [1, 2]. A critical stromal component for tumorigenesis is cancer-associated fibroblasts (CAFs). Following neoplastic transformation of epithelia, CAFs have been shown to promote tumor growth by inducing angiogenesis, inflammation, recruiting bone marrow–derived immunosuppressive cells, and remodeling the ECM [6, 7]. In cancers that present an extensive stroma reaction ( called desmoplasia), including pancreatic, breast, prostate or skin cancer, CAFs represent the major stromal cell population. By secreting pro-inflammatory factors as soon as the initiating hyperplastic phase of neoplasia, CAFs dialogue with epithelial cells to promote tumorigenesis [11]. This suggests that the therapeutic targeting of this cell population represents a promising strategy
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