Tumour-intrinsic interferon regulates bone-metastatic outgrowth from dormancy in prostate cancer

Identification: 4039


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Tumour-intrinsic interferon regulates bone-metastatic outgrowth from dormancy in prostate cancer

Katie Owen1, Marek Cmero2,3, Weng Hua Khoo4, Peter Croucher4, Alex Swarbrick4, Chris Hovens2, Niall Corcoran2, Nikola Baschuk1, Belinda Parker1

1Dept of Biochemistry and Genetics, La Trobe Institute for Molecular Science, Melbourne, VIC 2 Dept of Surgery, Division of Urology, RMH, VIC 3 WEHI, Parkville, VIC 4 Garvan Institute of Medical Research, Sydney, NSW

Bone metastasis in prostate cancer can occur up to 20 years after primary tumour diagnosis. This latency has been attributed to dormancy – a state in which tumour cells can survive undetected for prolonged periods. One mechanism proposed to induce tumour cell dormancy in bone is immune surveillance, with metastatic outgrowth requiring tumour cell-driven immune evasion strategies. Our lab has identified that immune evasion in breast cancer may be facilitated by tumour cell loss of interferon (IFN) signaling. We have now shown that IFN signaling is significantly suppressed in bone metastases compared to matched primary tumours in prostate cancer patients. To interrogate the timing of this loss we used the murine C57BL/6 RM model of prostate cancer linked to a cell labelling technique to FACS-purify dormant and proliferating RM1 cells from bone for RNA sequencing. Single-cell analysis revealed that IFN signaling was retained in dormant cells, yet significantly downregulated in active RM1 cells from bone. Suppression IFN signaling in active RM1 cells was also shown to be bone-specific, as loss was not observed in primary tumours and RM1 cells derived from other metastatic sites. Furthermore, we revealed that a loss of tumour-intrinsic IFN signaling significantly accelerated metastasis to bone, while overcoming this loss via systemic treatment with IFN inducers was sufficient to significantly delay bone metastasis onset. These results suggest that tumour cell loss of IFN signaling occurs specifically in the bone microenvironment and is a critical driver of metastatic outgrowth. This work may be exploited therapeutically to decrease bone metastasis and potentially reduce patient mortality in prostate cancer.

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