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

• Published in: Proceedings of the National Academy of Sciences - PNAS 2020-04, Vol.117 (15), p.8515-8523
• Main Authors: Haldar, Subhash, Mishra, Rajeev, Billet, Sandrine, Thiruvalluvan, Manish, Placencio-Hickok, Veronica R., Madhav, Anisha, Duong, Frank, Angara, Bryan, Agarwal, Priyanka, Tighiouart, Mourad, Posadas, Edwin M., Bhowmick, Neil A.
• Format: Article
• Language: English
• Subjects: Anaphylatoxins; Biological Sciences; Cancer; Catalase; Coevolution; Complement component C3; Complement component C3a; Complement receptors; Deoxyribonucleic acid; DNA; Fibroblasts; Maturation; Mitochondrial DNA; NF-κB protein; Paracrine signalling; Pattern recognition; PNAS Plus; Prostate cancer; Receptors; Recombination; Signaling; Taxanes; TLR9 protein; Toll-like receptors; Tumor cells; Tumors
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1910952117

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.