Poster Presentation & Flash Talk Presentation 29th Lorne Cancer Conference 2017

Tumour-intrinsic interferon signalling regulates bone-metastatic outgrowth from dormancy in prostate cancer (#33)

Katie L Owen 1 , Marek Cmero 2 3 4 , Niall Corcoran 2 , Chris Hovens 2 , Weng Hua Khoo 5 , Alex Swarbrick 5 , Peter Croucher 5 , Nikola Baschuk 1 , Belinda Parker 1
  1. Latrobe Institute For Molecular Science, Bundoora, VIC, Australia
  2. Department of Surgery, Division of Urology, Royal Melbourne Hospital, Melbourne, VIC, Australia
  3. Department of Computing & Information Systems, University of Melbourne, Melbourne, VIC, Australia
  4. Walter and Eliza Hall Institute, Melbourne, VIC, Australia
  5. Garvan Institute of Medical Research, Sydney, NSW, Australia

Bone metastasis in advanced prostate cancer can occur up to 20 years after primary tumour diagnosis and curative treatment. The latency associated with bone metastasis has been largely attributed to tumour cell dormancy – a state in which tumour cells or small colonies can survive undetected for prolonged periods. One mechanism proposed to induce dormancy in tumour cells within bone is immune surveillance, suggesting metastatic outgrowth may require tumour cell-driven immune evasion strategies. Our lab has identified that immune evasion and subsequent metastasis in breast cancer may be facilitated by tumour cell suppression of type I Interferon (IFN) signalling via the downregulation of key IFN regulatory factors (Irfs), including Irf7 and 9. Importantly, we have now demonstrated that IFN signalling is significantly suppressed in bone metastases compared to matched primary tumours in prostate cancer patients. To interrogate the timing of this loss we utilised the murine C57BL/6 RM model of prostate cancer linked to a cell labelling technique to identify and FACS-purify dormant and proliferating prostate cancer cells from bone for RNA sequencing. Single-cell analysis revealed that the expression of several key mediators of IFN signalling were retained in dormant, yet significantly downregulated in active RM cells derived from bone metastases. Suppression of tumour-intrinsic IFN signalling in active RM cells was also shown to be bone-specific, compared to primary tumours and RM cells derived from other metastatic sites and could be induced within just 48 hours of tumour-cell contact with the bone marrow. Furthermore, it was shown that a loss of tumour-intrinsic IFN signalling significantly accelerates prostate cancer progression to bone, while overcoming tumour cell loss of IFN signalling via systemic treatment with IFN inducers was sufficient to delay the onset and degree of tumour burden in bone. Overall, these novel results suggest that a loss tumour-intrinsic IFN signalling occurs specifically in the bone microenvironment and is a critical event preceding metastatic outgrowth from dormancy. This work may be exploited therapeutically to decrease bone-metastatic outgrowth in prostate cancer which could ultimately lead to reduced patient mortality.