Regulation of Tumor Progression Through Spatial Programs of Extracellular DNA Clearance and TLR9-Mediated Cancer Cell Senescence

Abstract

Premalignant tumors like ductal carcinoma in situ (DCIS) often harbor senescent cancer cells, but how senescence is induced or bypassed in invasive ductal carcinoma (IDC) remains unclear. In a murine breast cancer model, fewer senescent cells in IDC correlated with elevated extracellular DNase1L3. Its loss led to further increased immunoglobulin levels in IDC and systemic autoantibodies, including anti-nucleosome and anti-DNA antibodies. Depleting DNase1L3 and immunoglobulins extended senescence from DCIS to IDC. Similarly, cancer cell cultures exposed to apoptotic bodies underwent senescence. In both models, senescence required the endosomal DNA sensor TLR9 and signaling adaptor MyD88, but not the cytosolic DNA sensor cGAS. TLR9-driven senescence was also observed in human breast cancer cell cultures, and enriched in DCIS but not IDC, inversely correlating with DNase1L3 and immunoglobulin deposition. Thus, spatial variation in extracellular DNA clearance regulates DCIS-to-IDC progression by modulating TLR9-mediated cancer cell senescence as a tissue-level innate immune defense response.

Note:
Funding Information: We acknowledge the use of the Integrated Genomics Operation Core, Flow Cytometry Core, and Molecular Cytology Core, funded by the NCI Cancer Center Support Grant (CCSG, P30 CA0848). This work was supported by the National Institutes of Health (R01 CA198280, R01CA272717 to M.O.L.), MSKCC Alan and Sandra Gerry Metastasis and Tumor Ecosystems Center, and the Mazumdar-Shaw Translational Research Initiative in Kidney Cancer. SC is supported by the BCRF.

Declaration of Interests: M.O.L. is a scientific advisory board member of and holds equity or stock in Amberstone Biosciences and META Pharmaceuticals. S.W. provides consulting services and holds equity in Oric Pharmaceuticals, Blueprint Medicines, Mirimus Inc., Senecea Therapeutics, Faeth Therapeutics, and PMV Pharmaceuticals. S.C. has received institutional grant/funding from Daiichi-Sankyo and AstraZeneca, Share options in Totus Medicines, and consultation/Ad board/Honoraria from Daiichi-Sankyo, AstraZeneca, Lilly, Casdin Capital, and Pathos AI. F.P. provides consulting services to Multiplex Dx and AstraZeneca. All other authors have no competing interests.

Ethics Approval Statement: All animal experiments were conducted in accordance with procedures approved by the Institutional Animal Care and Use Committee of Memorial Sloan Kettering Cancer Center.

Keywords: Cellular senescence, premalignant tumor, invasive carcinoma, extracellular DNA, TLR9