Metastases arise from residual disseminated tumour cells (DTCs). This can happen years after primary tumour treatment because residual tumour cells can enter dormancy and evade therapies. As the biology of minimal residual disease seems to diverge from that of proliferative lesions, understanding the underpinnings of this new cancer biology is key to prevent metastasis. Analysis of approximately 7 years of literature reveals a growing focus on tumour and normal stem cell quiescence, extracellular and stromal microenvironments, autophagy and epigenetics as mechanisms that dictate tumour cell dormancy. In this Review, we attempt to integrate this information and highlight both the weaknesses and the strengths in the field to provide a framework to understand and target this crucial step in cancer progression.

In patients non-proliferative disseminated tumour cells (DTCs) can persist in the bone marrow (BM) while other organs (i.e. lung) present growing metastasis. This suggested that the BM might be a metastasis “restrictive soil” by encoding dormancy-inducing cues in DTCs. Here we show in a HNSCC model that strong and specific TGFβ2 signalling in the BM activates p38α/β, inducing a [ERK/p38]low signalling ratio. This results in induction of DEC2/SHARP1 and p27, downregulation of CDK4 and dormancy of malignant DTCs. TGFβ2-induced dormancy required TGFβ-receptor-I, TGFβ-receptor-III and SMAD1/5 activation to induce p27. In lungs, a metastasis “permissive soil” with low TGFβ2 levels, DTC dormancy was short lived and followed by metastatic growth. Importantly, systemic inhibition of TGFβ-receptor-I or p38α/β activities awakened dormant DTCs fueling multi-organ metastasis. Our work reveals a “seed and soil” mechanism where TGFβ2 and TGFβRIII signalling through p38α/β regulates DTC dormancy and defines restrictive (BM) and -permissive (lung) microenvironments for HNSCC metastasis.

Metastases can originate from disseminated tumor cells (DTCs), which may be dormant for years before reactivation. Here we find that the orphan nuclear receptor NR2F1 is epigenetically upregulated in experimental HNSCC dormancy models and in DTCs from prostate cancer patients carrying dormant disease for 7–18 years. NR2F1-dependent dormancy is recapitulated by a co-treatment with the DNA demethylating agent 5-Aza-C and retinoic acid across various cancer types. NR2F1-induced quiescence is dependent on SOX9, RARβ and CDK inhibitors. Intriguingly, NR2F1 induces global chromatin repression and the pluripotency gene NANOG, which contributes to dormancy of DTCs in the bone marrow. When NR2F1 is blocked in vivo, growth arrest or survival of dormant DTCs is interrupted in different organs. We conclude that NR2F1 is a critical node in dormancy induction and maintenance by integrating epigenetic programs of quiescence and survival in DTCs.

Cisplatin is one of the major chemotherapeutic weapons used against different human cancers, although its mechanism to induce apoptosis is not fully understood. The presence of wild type p53 has been suggested to be important for cisplatin cytotoxicity, hence we found that cisplatin induced apoptosis in cell lines with functional p53. Using the HCT116 colon carcinoma derived cell line we have established that the apoptotic activity of cisplatin requires the onset of a p53-mediated p38alpha MAPK pathway through generation of reactive oxygen species (ROS). HCT116 p53-deficient cells were much less sensitive to apoptosis by cisplatin than their p53wt counterparts, where apoptosis was strongly inhibited by antioxidants. Moreover, the presence of pifithrin-alpha, an inhibitor of p53 transcriptional activity, blocked cisplatin-induced apoptosis, reduced the generation of ROS produced upon cisplatin treatment. In addition, we have identified p38alpha as the isoform necessary for cisplatin-induced apoptosis, upon activation by p53-mediated ROS production. p38alpha MAPK contributes to further activation of p53, which leads to a positive feedback loop, p38alpha MAPK/p53. We conclude that the p53/ROS/p38alpha MAPK cascade is essential for cisplatin-induced cell death in HCT116 cells and the subsequent p38alpha/p53 positive feedback loop strongly enhances the initial p53 activation.