The biological complexity of cancer represents a tremendous clinical challenge, resulting in the frequent failure of current treatment protocols. In the rapidly evolving scenario of a growing tumor, anticancer treatments impose a drastic perturbation not only to cancer cells but also to the tumor microenvironment, killing a portion of the cells and inducing a massive stress response in the survivors. Consequently, treatments can act as a double-edged sword by inducing a temporary response while laying the ground for therapy resistance and subsequent disease progression. Cancer cell dormancy (or quiescence) is a central theme in tumor evolution, being tightly linked to the tumor’s ability to survive cytotoxic challenges, metastasize, and resist immune-mediated attack. Accordingly, quiescent cancer cells (QCCs) have been detected in virtually all the stages of tumor development. In recent years, an increasing number of studies have focused on the characterization of quiescent/therapy resistant cancer cells, unveiling QCCs core transcriptional programs, metabolic plasticity, and mechanisms of immune escape. At the same time, our partial understanding of tumor quiescence reflects the difficulty to identify stable QCCs biomarkers/therapeutic targets and to control cancer dormancy in clinical settings. This review focuses on recent discoveries in the interrelated fields of dormancy, stemness, and therapy resistance, discussing experimental evidences in the frame of a nonlinear dynamics approach, and exploring the possibility that tumor quiescence may represent not only a peril but also a potential therapeutic resource.

Quiescent cancer cells (QCCs) are a common feature of solid tumors, representing a major obstacle to the long-term success of cancer therapies. We isolated QCCs ex vivo from non-small cell lung cancer (NSCLC) and colorectal cancer (CRC) xenografts with a label-retaining strategy and compared QCCs gene expression profiles to identify a shared “quiescence signature”. Principal Component Analysis (PCA) revealed a specific component neatly discriminating quiescent and replicative phenotypes in NSCLC and CRC. The discriminating component showed significant overlapping, with 688 genes in common including ZEB2, a master regulator of stem cell plasticity and epithelial-to-mesenchymal transition (EMT). Gene set enrichment analysis showed that QCCs of both NSCLC and CRC had an increased expression of factors related to stemness/self renewal, EMT, TGF-β, morphogenesis, cell adhesion and chemotaxis, whereas proliferating cells overexpressed Myc targets and factors involved in RNA metabolism. Eventually, we analyzed in depth by means of a complex network approach, both the ‘morphogenesis module’ and the subset of differentially expressed genes shared by NCSLC and CRC. This allowed us to recognize different gene regulation network wiring for quiescent and proliferating cells and to underpin few genes central for network integration that may represent new therapeutic vulnerabilities. Altogether, our results highlight common regulatory pathways in QCCs of lung and colorectal tumors that may be the target of future therapeutic interventions.

Background/Objectives: Cochlear implants (CIs) and other implantable hearing devices are crucial to treat hearing loss. The aim of this study was to analyze the temporal trends of implantation for hearing devices in Italy between 2001 and 2023, with stratification by age. Methods: This population-based study explored Hospital Discharge Records and used codes from the International Classification of Diseases, 9th revision—Clinical Modification (ICD9-CM) to identify cochlear and non-cochlear implants. Patients were partitioned into six age classes: 80; and time series for counts and incidence rates (IRs) per 1,000,000 inhabitants with confidence intervals (CI_95%) were explored overall and by age class. Trends were assessed by incidence rate ratio and Cox–Stuart test with a significance threshold for p-values at 0.05. Results: 22,850 (83.6%) records for cochlear and 4476 (16.4%) for non-cochlear implants were extracted. Cochlear implants volume shifted from 537 procedures in 2001 to 1595 in 2023 (p < 0.01), while IR increased (p < 0.01) from 9.4 (CI_95%: 9.7, 10.3) in 2001 to 27 (CI_95%: 25.7, 28.4) in 2023. The volumes of implanted CIs increased in children and adults. Volumes for non-cochlear implants increased between 2001 and 2010, from 62 to 254, and remained stable afterwards. IR shifted from 1.1 (CI_95%: 0.8, 1.4) in 2001 to 4.1 (CI_95%: 3.6, 4.7) in 2023. Conclusions: Those trends highlight the importance of monitoring efficacy and safety of hearing devices, and the establishment of the Italian Implantable Hearing Device Registry at the Italian National Institute of Health is a first step in such a direction.