RIPK3 upregulation confers robust proliferation and collateral cystine-dependence on breast cancer recurrence

Abstract

26The molecular and genetic basis of tumor recurrence is complex and poorly 27 understood. RIPK3 is a key effector in programmed necrotic cell death and, therefore, 28 its expression is frequently suppressed in primary tumors. In a transcriptome profiling 29 between primary and recurrent breast tumor cells from a murine model of breast 30 cancer recurrence, we found that RIPK3, while absent in primary tumor cells, is 31 dramatically re-expressed in recurrent breast tumor cells by an epigenetic mechanism. 32 Unexpectedly, we found that RIPK3 knockdown in recurrent tumor cells reduced 33 clonogenic growth, causing cytokinesis failure, p53 stabilization, and repressed the 34 activities of YAP/TAZ. These data uncover a surprising role of the pro-necroptotic 35 RIPK3 kinase in enabling productive cell cycle during tumor recurrence. Remarkably, 36 high RIPK3 expression also rendered recurrent tumor cells exquisitely dependent on 37 extracellular cystine and undergo programmed necrosis upon cystine deprivation. The 38 induction of RIPK3 in recurrent tumors unravels an unexpected mechanism that 39 paradoxically confers on tumors both growth advantage and necrotic vulnerability, 40 providing potential strategies to eradicate recurrent tumors. 41 42 43 44 45 46 47 48While significant progress has been made for the diagnosis and treatment of 52 primary tumors, the emergence of recurrent tumors after the initial response to 53 treatments still poses significant clinical challenges. Recurrent breast tumors are 54 generally incurable and unresponsive to the treatments effective for primary tumors 1 . 55Several factors have shown to be associated with breast tumor recurrence, including 56 the age when primary tumor is diagnosed 2, 3 , lymph node status, tumor size, 57 histological grade 4, 5, 6 , the status of estrogen receptor (ER), progesterone receptor 58 (PR) and the expression of human epidermal growth factor receptor 2 (HER2) 7, 8, 9 . 59 However, the molecular and genetic events that lead to tumor recurrence remain 60 largely unknown. 61To study the mechanism of tumor recurrence, genetically engineered mouse 62 (GEM) models of recurrent breast cancers have been established. Utilizing the 63 doxycycline-inducible system, the expression of specific oncogenes can be 64 conditionally expressed and withdrawn in the mammary gland 10, 11, 12, 13, 14 . In the bi-65 transgenic mice expressing an MMTV-rtTA (MTB) and inducible Neu (homolog of 66 HER2) oncogene (TetO-neu; TAN), mammary adenocarcinomas can be induced by 67 the administration of doxycycline and regressed after doxycycline withdrawal 10, 11, 12, 68 13, 14 . Importantly, the recurrent tumors will eventually emerge in most mice after the 69 expression of the oncogene is turned off 10, 11, 12, 13, 14 . This tumor recurrent model 70 bears significant similarities to human breast cancer recurrence in several important 71 ways: (1) Tumor recurrence occurs over a long timeframe relative to the lifespan of 72 the mouse, similar to the timing of recurrences in h...

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“…RIPK3, a key effector in programmed necrotic cell death, was found to be overexpressed in recurrent breast tumour cells from a murine model of breast cancer recurrence. The upregulated expression of RIPK3 caused the recurrent tumour cells to rely on extracellular cystine and undergo necroptosis and ferroptosis upon cystine deprivation with erastin [146].…”

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