Modelling Circulating Tumour Cells for Personalised Survival Prediction in Metastatic Breast Cancer

Abstract

Ductal carcinoma is one of the most common cancers among women, and the main cause of death is the formation of metastases. The development of metastases is caused by cancer cells that migrate from the primary tumour site (the mammary duct) through the blood vessels and extravasating they initiate metastasis. Here, we propose a multi-compartment model which mimics the dynamics of tumoural cells in the mammary duct, in the circulatory system and in the bone. Through a branching process model, we describe the relation between the survival times and the four markers mainly involved in metastatic breast cancer (EPCAM, CD47, CD44 and MET). In particular, the model takes into account the gene expression profile of circulating tumour cells to predict personalised survival probability. We also include the administration of drugs as bisphosphonates, which reduce the formation of circulating tumour cells and their survival in the blood vessels, in order to analyse the dynamic changes induced by the therapy.We analyse the effects of circulating tumour cells on the progression of the disease providing a quantitative measure of the cell driver mutations needed for invading the bone tissue. Our model allows to design intervention scenarios that alter the patient-specific survival probability by modifying the populations of circulating tumour cells and it could be extended to other cancer metastasis dynamics.

Signatures of breast cancer metastasis at a glance

“…When coupled to high-throughput microarray or RNAsequencing technologies and unbiased bioinformatics analyses, the aforementioned obstacles are significantly surmounted (Curtis, 2015;Magbanua and Park, 2014). Overall, these new-generation studies have allowed single-cell and bulk-cell analyses of CTCs, which efficiently capture the transcriptional heterogeneity and identify the molecular portraits of metastasizing cells (Ascolani et al, 2015;Cassatella et al, 2012;De Mattos-Arruda et al, 2013;Fina et al, 2015;Lang et al, 2015;Polzer et al, 2014;Powell et al, 2012). For example, one study has demonstrated that CTCs express various biomarkers and mediators of EMT (Yu et al, 2013), a phenotypic change crucial for the completion of the metastatic cascade (Bill and Christofori, 2015;Hanahan and Weinberg, 2011;Kalluri, 2009;Kalluri and Weinberg, 2009;Radaelli et al, 2009).…”

Modeling the Human Bone–Tumor Niche: Reducing and Replacing the Need for Animal Data

“…(45) Models of breast cancer consisting of three compartments: the primary tumor, the circulatory system, and bone as the site of distant metastasis, have been proposed. (63) Such models could be useful in determining which treatment strategies would best help to reduce metastasis by targeting the tumor cells in the circulatory compartment.…”

“…In addition, the simulation of breast cancer cells in an extracellular matrix revealed that the activity of membrane‐bound enzyme MT1‐MMP plays a more important role in tumor invasion, compared with secreted matrix‐degrading enzymes such as MMP9 . Models of breast cancer consisting of three compartments: the primary tumor, the circulatory system, and bone as the site of distant metastasis, have been proposed . Such models could be useful in determining which treatment strategies would best help to reduce metastasis by targeting the tumor cells in the circulatory compartment.…”

Nowotworowe komórki krążące: biologia i znaczenie kliniczne

“…Wykazano przydatność oznaczania liczby CTC w krwi obwodowej do przewidywania odpowiedzi klinicznej, zwłaszcza u chorych przed zastosowaniem leczenia systemowego (2). Analiza CTC po poszczególnych etapach leczenia stanowi marker odpowiedzi na zastosowaną terapię (3). Ponadto, z uwagi na fakt, że CTC są frakcją komórek pochodzącą bezpośrednio z ogniska pierwotnego, mogą one stanowić idealny model do badań in vitro biologii nowotworu (4).…”