Cellular senescence is a complex cell state that can occur during physiological ageing or after exposure to stress signals, regardless of age. It is a dynamic process that continuously evolves in a context-dependent manner. Senescent cells interact with their microenvironment by producing a heterogenous and plastic secretome referred to as the senescence-associated secretory phenotype (SASP). Hence, understanding the cross-talk between SASP and the microenvironment can be challenging due to the complexity of signal exchanges. In this review, we first aim to update the definition of senescence and its associated biomarkers from its discovery to the present day. We detail the regulatory mechanisms involved in the expression of SASP at multiple levels and develop how SASP can orchestrate microenvironment modifications, by focusing on extracellular matrix modifications, neighboring cells’ fate, and intercellular communications. We present hypotheses on how these microenvironmental events may affect dynamic changes in SASP composition in return. Finally, we discuss the various existing approaches to targeting SASP and clarify what is currently known about the biological effects of these modified SASPs on the cellular environment.

Ets-1 transcription factor overexpression in breast cancers is associated with invasive features and is associated with a poor prognosis. Beyond its role in driving carcinoma cell invasion, in this study, we wished to determine whether Ets-1 overexpression in cancer cells promotes angiogenesis by creating a paracrine pro-invasive environment for endothelial cells as well. To address this question, we set up different co-culture models of cancer cells with endothelial cells. Conditioned media from cancer cells induced endothelial cell proliferation, migration and morphogenesis in matrix models. Of note, co-culture assays in three-dimensional matrix models also revealed the reciprocal induction of cancer cell morphogenesis by endothelial cells, in support of an angiocrine action on tumor cells. Ets-1 emerged as a key regulator of the angiogenic potential of breast cancer cells, favoring their ability to induce, in a paracrine manner, the morphogenesis of endothelial cells and also to physically interact with the latter. Nevertheless, Ets-1 overexpression in cancer cells also restrained their chemoattractive potential for endothelial cells both in Boyden chambers and in ex vivo 3D co-cultures. Finally, Ets-1 modulation in breast cancer cells qualitatively altered the angiogenic pattern of experimental in vivo tumors, with a balance between vessel recruitment and intratumoral small capillaries sprouting. Taken together, our data highlight a critical and intriguing role for Ets-1 in the angiogenic potential of breast cancer cells, and reveal another facet of Ets-1 oncogenic activities.

Senescent cells have been recognized to play major roles in tumor progression and are nowadays included in the hallmarks of cancer.Our work aims to develop a mathematical model capable of capturing a pro-invasion effect of senescent fibroblasts located in the conjunctive tissue. We focus in the present article on the first moments of the invasion cascade. Considering a localized epithelial tumor, we model the digestion of the collagen fibers of the basement membrane by the proteolytic enzyme MMP-2. The activation of MMP-2 is modelled in detail, as MT1-MMPs bound to the surface of tumor cells interact with proMMPs and TIMPs, proteins enriched in the secretome of senescent Cancer-Associated Fibroblasts, along with its inhibition by TIMPs. Using numerical simulations of the model, calibrated via an extensive literature search, reproducing biologically relevant scenarios, we test the model’s suitability to investigate the effect on basement membrane digestion of fibroblasts presenting a senescence-associated secretory phenotype. Via model reduction, steady state and global sensitivity analyses, we identify the most influential parameters in view of their calibration with empirical data. We conclude the paper discussing mathematical and interdisciplinary perspectives.