Cancer epithelia-derived mitochondrial DNA is a targetable initiator of a paracrine signaling loop that confers taxane resistance

Abstract

Stromal-epithelial interactions dictate cancer progression and therapeutic response. Prostate cancer (PCa) cells were identified to secrete greater concentration of mitochondrial DNA (mtDNA) compared to noncancer epithelia. Based on the recognized coevolution of cancer-associated fibroblasts (CAF) with tumor progression, we tested the role of cancer-derived mtDNA in a mechanism of paracrine signaling. We found that prostatic CAF expressed DEC205, which was not expressed by normal tissue-associated fibroblasts. DEC205 is a transmembrane protein that bound mtDNA and contributed to pattern recognition by Toll-like receptor 9 (TLR9). Complement C3 was the dominant gene targeted by TLR9-induced NF-κB signaling in CAF. The subsequent maturation complement C3 maturation to anaphylatoxin C3a was dependent on PCa epithelial inhibition of catalase in CAF. In a syngeneic tissue recombination model of PCa and associated fibroblast, the antagonism of the C3a receptor and the fibroblastic knockout of TLR9 similarly resulted in immune suppression with a significant reduction in tumor progression, compared to saline-treated tumors associated with wild-type prostatic fibroblasts. Interestingly, docetaxel, a common therapy for advanced PCa, further promoted mtDNA secretion in cultured epithelia, mice, and PCa patients. The antiapoptotic signaling downstream of anaphylatoxin C3a signaling in tumor cells contributed to docetaxel resistance. The inhibition of C3a receptor sensitized PCa epithelia to docetaxel in a synergistic manner. Tumor models of human PCa epithelia with CAF expanded similarly in mice in the presence or absence of docetaxel. The combination therapy of docetaxel and C3 receptor antagonist disrupted the mtDNA/C3a paracrine loop and restored docetaxel sensitivity.

Inside-Out of Complement in Cancer

“…Upon this stimulation, fibroblasts secrete C3a in reactive oxygen species (ROS) dependent manner. Then C3a in a paracrine fashion promotes disease progression and docetaxel resistance by increasing tumor cell proliferation and survival ( 103 ). In a subcutaneous xenograft of human PC3 prostate cell line, the authors demonstrated superior efficacy of docetaxel and C3aR inhibition over docetaxel alone in decreasing tumor burden.…”

Deconstructing tumor heterogeneity: the stromal perspective

“…Interestingly, C3a-induced activation of the C3a receptor in prostate cancer cells drives docetaxel resistance in mouse models. mtDNA was also found in the plasma of docetaxel-treated patients supporting the hypothesis that therapy resistance in prostate cancer patients may occur by this crosstalk [63]. In mouse models, combination therapy of docetaxel with a C3aR inhibitor showed increased efficacy in limiting tumor growth when compared to docetaxel alone.…”

“…Neil Bhowmick expanded on the stromal considerations for prostate cancer therapy by presenting findings that demonstrated chemotherapy-triggered crosstalk between CAFs and tumor cells. His team found that docetaxel induces mitophagy and ER stress in prostate tumor cells, leading to secretion of mitochondrial DNA (mtDNA) [63]. This results in TLR9 activation in CAFs and release of C3a, a complement protein.…”

Myeloid Responses to Extracellular Vesicles in Health and Disease

“…Mt-DNA has been shown to induce TLR9-mediated NF-κB activation driving regulatory polarization in macrophages in liver cancer ( 59 ) as well as activation of neutrophils in various forms of injury ( 60 ). Further, non-immune cancer-associated fibroblasts were also shown respond to mt-DNA via TLR-9 contributing to therapeutic resistance to taxanes ( 40 ). In addition to inflammatory modulation, mutations in tumor mt-DNA can also regulate mitochondrial metabolism in recipient cells ( 61 ) but have not been well-studied in the context of myeloid immunity.…”