A three-marker signature identifies senescence in human breast cancer exposed to neoadjuvant chemotherapy.

PURPOSE: Despite the beneficial effects of chemotherapy, therapy-induced senescence (TIS) manifests itself as an undesirable byproduct. Preclinical evidence suggests that tumor cells undergoing TIS can re-emerge as more aggressive divergents and contribute to recurrence, and thus, senolytics were proposed as adjuvant treatment to eliminate senescent tumor cells. However, the identification of TIS in clinical samples is essential for the optimal use of senolytics in cancer therapy. In this study, we aimed to detect and quantify TIS using matched breast cancer samples collected pre- and post-exposure to neoadjuvant chemotherapy (NAC). METHODS: Detection of TIS was based on the change in gene and protein expression levels of three senescence-associated markers (downregulation of Lamin B1 and Ki-67 and upregulation of p16INK4a). RESULTS: Our analysis revealed that 23 of 72 (31%) of tumors had a shift in the protein expression of the three markers after exposure to NAC suggestive of TIS. Gene expression sets of two independent NAC-treated breast cancer samples showed consistent changes in the expression levels of LMNB1, MKI67 and CDKN2A. CONCLUSIONS: Collectively, our study shows a more individualized approach to measure TIS hallmarks in matched breast cancer samples and provides an estimation of the extent of TIS in breast cancer clinically. Results from this work should be complemented with more comprehensive identification approaches of TIS in clinical samples in order to adopt a more careful implementation of senolytics in cancer treatment.

Can 3D bioprinting solve the mystery of senescence in cancer therapy?

Tumor dormancy leading to cancer relapse is still a poorly understood mechanism. Several cell states such as quiescence and diapause can explain the persistence of tumor cells in a dormant state, but the potential role of tumor cell senescence has been met with hesitance given the historical understanding of the senescent growth arrest as irreversible. However, recent evidence has suggested that senescence might contribute to dormancy and relapse, although its exact role is not fully developed. This limited understanding is largely due to the paucity of reliable study models. The current 2D cell modeling is overly simplistic and lacks the appropriate representation of the interactions between tumor cells (senescent or non-senescent) and the other cell types within the tumor microenvironment (TME), as well as with the extracellular matrix (ECM). 3D cell culture models, including 3D bioprinting techniques, offer a promising approach to better recapitulate the native cancer microenvironment and would significantly improve our understanding of cancer biology and cellular response to treatment, particularly Therapy-Induced Senescence (TIS), and its contribution to tumor dormancy and cancer recurrence. Fabricating a novel 3D bioprinted model offers excellent opportunities to investigate both the role of TIS in tumor dormancy and the utility of senolytics (drugs that selectively eliminate senescent cells) in targeting dormant cancer cells and mitigating the risk for resurgence. In this review, we discuss literature on the possible contribution of TIS in tumor dormancy, provide examples on the current 3D models of senescence, and propose a novel 3D model to investigate the ultimate role of TIS in mediating overall response to therapy.