SULF1 suppresses Wnt3A-driven growth of bone metastatic prostate cancer in perlecan-modified 3D cancer-stroma-macrophage triculture models

Abstract

Bone marrow stroma influences metastatic prostate cancer (PCa) progression, latency, and recurrence. At sites of PCa bone metastasis, cancer-associated fibroblasts and tumor-associated macrophages interact to establish a perlecan-rich desmoplastic stroma. As a heparan sulfate proteoglycan, perlecan (HSPG2) stores and stabilizes growth factors, including heparin-binding Wnt3A, a positive regulator of PCa cell growth. Because PCa cells alone do not induce CAF production of perlecan in the desmoplastic stroma, we sought to discover the sources of perlecan and its growth factor-releasing modifiers SULF1, SULF2, and heparanase in PCa cells and xenografts, bone marrow fibroblasts, and macrophages. SULF1, produced primarily by bone marrow fibroblasts, was the main glycosaminoglycanase present, a finding validated with primary tissue specimens of PCa metastases with desmoplastic bone stroma. Expression of both HSPG2 and SULF1 was concentrated in αSMA-rich stroma near PCa tumor nests, where infiltrating pro-tumor TAMs also were present. To decipher SULF1's role in the reactive bone stroma, we created a bone marrow biomimetic hydrogel incorporating perlecan, PCa cells, macrophages, and fibroblastic bone marrow stromal cells. Finding that M2-like macrophages increased levels of SULF1 and HSPG2 produced by fibroblasts, we examined SULF1 function in Wnt3A-mediated PCa tumoroid growth in tricultures. Comparing control or SULF1 knockout fibroblastic cells, we showed that SULF1 reduces Wnt3A-driven growth, cellularity, and cluster number of PCa cells in our 3D model. We conclude that SULF1 can suppress Wnt3A-driven growth signals in the desmoplastic stroma of PCa bone metastases, and SULF1 loss favors PCa progression, even in the presence of pro-tumorigenic TAMs.

The transcriptional landscape and biomarker potential of circular RNAs in prostate cancer

“…The oxidase SULF1 has been shown to modulate growth factor and cytokine signaling and to hold tumor suppressor activity in breast, pancreas, kidney, and hepatocellular cancer cell lines [ 41 ]. Moreover, it has been reported that SULF1is downregulated in PC, where it has been suggested to inhibit growth of PC bone metastases [ 42 ]. The role of TULP4, MKLN1, and ZNF532 in cancer is largely unknown.…”

CAFs Interacting With TAMs in Tumor Microenvironment to Enhance Tumorigenesis and Immune Evasion

“…In addition, it was also reported that the primary tumor promoted fibroblast secretion of fibronectin, which took part in the recruitment of bone marrow derived macrophages to the secondary site in liver and lung metastases (322,324,326,327). In a recent study, CAFs and TAMs were reported to interact in generating a perlecan (a heparan sulfate proteoglycan that stores and stabilizes growth factors implicated in regulation of prostate cancer cell growth) rich desmoplastic stroma at sites of prostate cancer bone metastasis (328). Indeed, the complex trilateral crosstalk among cancer cells, CAFs and M2 macrophages may activate endothelial cells and their bone marrow derived precursors to induce de novo angiogenesis and promote metastatic spread of tumor cells (238).…”

Hydrogels to engineer tumor microenvironmentsin vitro

“…Using this tri-culture, M2-like macrophages were found to increase levels of SULF1 and HSPG2 in fibroblasts, and that SULF1 can mitigate Wnt3a-driven growth signals. 334 In another example, Rebelo and colleagues developed an alginate-based tri-culture of lung cancer cells, CAFs and monocytes and demonstrated that the model creates an immunosuppressive and invasive environment that activated monocytes towards TAMs. It should be noted that the TAM-like phenotype was observed only when all three cell types were in the tri-culture.…”