TimeTeller: a New Tool for Precision Circadian Medicine and Cancer Prognosis

Abstract

Recent studies have established that the circadian clock influences onset, progression and therapeutic outcomes in a number of diseases including cancer and heart disease. Therefore, there is a need for tools to measure the functional state of the circadian clock and its downstream targets in patients. We provide such a tool and demonstrate its clinical relevance by an application to breast cancer where we find a strong link between survival and our measure of clock dysfunction. We use a machine-learning approach and construct an algorithm called TimeTeller which uses the multi-dimensional state of the genes in a transcriptomics analysis of a single biological sample to assess the level of circadian clock dysfunction. We demonstrate how this can distinguish healthy from malignant tissues and demonstrate that the molecular clock dysfunction metric is a potentially new prognostic and predictive breast cancer biomarker that is independent of the main established prognostic factors.

Chronic circadian disruption modulates breast cancer stemness and immune microenvironment to drive metastasis in mice

“…In addition to epidemiological studies, there is a growing body of experimental evidence linking circadian disruption to increased breast cancer risk and poorer survival outcome 6,8,45,46 . Here, we present findings showing that chronic CRD favours cancer-cell dissemination and metastasis formation, and we shed light on the underlying cellular and molecular alterations.…”

“…Recent studies have also suggested the use of CXCR2 or CXCR4 inhibitors in combination with immunotherapy to overcome therapeutic resistance 83,87 . These therapeutic strategies, together with the use of predictive tools based on clock-gene expression for cancer prognosis, will lead to precision circadian medicine with improved efficacy and responsiveness to immunotherapy 46,88 .…”

Chronic circadian disruption modulates breast cancer cell stemness and their immune microenvironment to drive metastasis in mice

“…82,88 These novel therapeutic strategies, together with the use of the new predictive tools based on clock genes expression for cancer prognosis will lead to a precision circadian medicine with improved efficacy and immunotherapy responsiveness. 39,89 In conclusion, our study provides for the first time experimental evidence of the link between CRD and an increase in cancer cell dissemination and metastasis formation. Here we propose two novel molecular mechanisms for how CRD promote tumorigenesis: 1) CRD increases the stemness and tumour-initiating potential of cancer cells, at least by promoting a pro-EMT intratumoral context and 2) CRD reduces anti-tumour immunity through modified chemokine/chemokine receptor signalling.…”

“…In correspondence to epidemiological studies, there is a growing body of experimental evidence linking circadian disruption to increased breast cancer risk and poorer survival outcome. 6,8,38,39 Here, we present original findings showing that chronic CRD favors cancer cell dissemination and metastasis formation and we shed light on the underlying cellular and molecular alterations. For this purpose we used the MMTV::PyMT spontaneous murine mammary carcinogenesis model, 15,40,41 which recapitulates many processes involved in human metastatic breast cancer.…”

How to tell time: advances in decoding circadian phase from omics snapshots

“…This renders the method inapplicable to most existing data and deeply constrains its use in a medical context. The latest, still unpublished, method, TimeTeller, is a supervised method that exploits the periodic expression and covariance of 10-15 key genes to infer external time from a single tissue sample 42 . A summary of the main characteristics of each of these methods is presented in Figure 2.…”