Peptide drug ablating adipose-derived cancer-associated fibroblasts suppresses pancreatic cancer aggressiveness
Introduction
Cancer-associated fibroblasts (CAFs) have been revealed as a heterogeneous pool of mesenchymal cells that modulate chemotherapy resistance, metastatic dissemination, and immunosuppression. During carcinoma progression, mesenchymal stromal cells (MSCs) become recruited to tumors and contribute to the pool of CAFs. These cells, undergoing age- and disease-associated changes, have incompletely understood effects on cancer aggressiveness. Overgrowth of white adipose tissue (WAT) in obesity has been uncovered as an important risk factor for carcinoma aggressiveness. We and others have reported that adipose stromal cells (ASCs), the MSCs/fibro-adipocyte progenitors of WAT, undergo mobilization in obesity and cancer. ASCs recruited from WAT, especially in the context of obesity, exacerbate tumor growth and promote the epithelial-mesenchymal transition (EMT). Several lineages of ASCs have been characterized, and their individual contributions to the distinct populations of CAFs and roles in cancer aggressiveness have remained debated.
Methods
Here, the role of CAFs derived from Pdgfra+ and Pdgfrb+ lineages was analyzed in mouse models of breast, prostate, and pancreatic cancer. We performed lineage tracing studies to assess the contribution of adipocyte-mesenchymal transition to aCAF generation. We used mouse models in which replicative senescence of MSCs was induced by deletion of telomerase (Tert) gene in Pdgfra+ and Pdgfrb+ lineage cells. With funds from a previous CPRIT High Risk/High Impact award, we have developed a peptide-drug conjugate D-CAN that can be used for experimental ASC depletion. In a series of studies, we have demonstrated that D-CAN synergizes with chemotherapy and suppresses metastatic cancer progression in mouse breast and prostate cancer models. Here, we used D-CAN treatment in animal cancer models to test if ablation of ASCs/aCAFs can suppress chemoresistant/immunosuppressive tumor microenvironment in pancreatic ductal adenocarcinoma (PDAC). We compared the effects to those induced by genetic ablation of Pdgfrb+ lineage MSCs via thymidine kinase/ganciclovir suicide gene system.
Results
We report that replicative senescence of Pdgfra+ and Pdgfrb+ lineage cells, induced by Ter knockout, results in reduced growth of allografted mouse tumors without metastasis induction. Ablation of adipose-derived CAFs with D-CAN in an orthotopic pancreatic cancer KPC graft model identified the role of ASC-derived CAFs in suppressing lymphocyte and macrophage infiltration. It also demonstrated that ASC-derived CAFs support endothelium and cancer cell survival. Genetic ablation of Pdgfrb+ lineage MSCs via thymidine kinase/ganciclovir confirmed that these cells suppress immune cell recruitment. However, Pdgfrb+ lineage stroma depletion resulted in the appearance of a cancer cell population hallmarked by expression of genes promoting cell proliferation and EMT, induction of which has been linked with decreased cancer patient survival. Importantly, pancreatic tumor growth suppression by Pdgfrb+ lineage stroma depletion was concomitant with induction of spontaneous liver metastases.
Conclusion
We conclude that MSC/ASC-derived CAFs in adenocarcinomas contribute to tumor growth and the establishment of immunosuppressive microenvironment. However, our data indicate that, in distinct types of cancer, subsets of CAFs may have different effects on cancer progression. Therefore, development of therapeutic approaches targeting mesenchymal stroma in tumors should be context dependent. Continuation of these studies will generate data instrumental for better understanding of mechanisms underlying PDAC progression and pave the path toward effective combination therapies.