Autocrine WNT Inhibition Drives Immune Evasion and Latency of Metastases

Patients with highly malignant tumors often relapse after treatment of the primary tumor due to metastatic colonization, which occurs prior to diagnosis. However, elucidation of the molecular mechanisms underlying disseminated tumor cell latency has been difficult due to the lack of adequate preclinical models. Malladi and colleagues injected nude mice with fluorescently labeled metastatic breast and lung cancer lines and isolated latency competent cancer (LCC) cells from target organs harvested before the appearance of overt tumors in most mice. Orthotopic implantation of LCC cells exhibited similar tumorigenic properties as the parental lines and greater metastasis-initiating potential. Pulse-chase experiments with a thymidine analogue revealed that LCC cells entered quiescence more frequently than the parental cells in vitro and in vivo. Depletion of natural killer (NK) cells resulted in outgrowth and increased metastases of lung LCC cells in vivo. Bioinformatic analyses of gene signatures showed that LCC cells closely resembled stem and progenitor cells, and that LCC exhibited decreased expression of NK cytotoxicity gene signatures. Consistent with these findings, LCC cells exhibited overexpression of SRY-box 2 (SOX2) and SOX9, two stem cell–associated transcription factors which were required for LCC oncosphere formation in vitro and metastatic seeding in vivo, and were resistant to NK-mediated cytolysis in vitro. Analysis of quiescent LCC cells revealed the reduction of WNT, MYC, and NFκβ signaling. Consistent with these findings, dickhopf WNT signaling pathway inhibitor 1 (DKK1) was expressed in LCC cells in vitro and in vivo, as well as in disseminated tumor cells which arose in mice orthotopically implanted with breast cancer patient-derived xenografts. Mechanistically, upregulation of SOX2 resulted in autocrine DKK1 expression, which attenuated WNT signaling to drive LCC cells into quiescence, which induced the downregulation of NK cell activators. Together, these results describe the autocrine mechanism by which disseminated tumor cells enter quiescence and evade immune surveillance while maintaining the potential for tumor initiation and outgrowth.

Malladi S, Macalinao DG, Jin X, He L, Basnet H, Zou Y, et al. Metastatic latency and immune evasion through autocrine inhibition of WNT. Cell 2016;165:45–60.

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