Intratumoral Senescence Drives Cancer Metastasis

Abstract

Cellular senescence is a stress-induced cell cycle arrest that can be triggered by various stimuli such as telomere shortening, oncogene activation, radiation or chemotherapy. Through their senescence-associated secretory phenotype (SASP), senescent cells shape their microenvironment and have both beneficial and detrimental effects, affecting processes such as tissue repair, inflammation and tumorigenesis. While extensive data exists on the role of therapy-induced senescent tumor and stromal cells, little is known about senescent cancer cells under therapy-naive conditions. The aim of this work was to characterize the role of spontaneously senescent tumor cells (SSTC) under therapy-naïve conditions. SSTC were found in therapy-naive murine and human colorectal carcinoma (CRC), cholangiocarcinoma (CCA) and pancreatic ductal adenocarcinoma (PDAC) as well as in 27 different human and murine tumor lines. Interestingly, the percentage of SSTCs within the lines correlated with their in vitro invasive capacity. Analysis of primary human tumor material also showed an increased frequency of SSTC in patients with regional lymph node metastasis compared to patients with localized disease. Pharmacological senolysis with navitoclax or genetic ablation of SSTC significantly reduced tumor cell invasion in vitro and in vivo, resulting in significantly reduced metastasis in the passive splenic seeding model and in two syngenic mouse models of CRC and CCA. Spontaneous senescence and tumor invasion/metastasis were shown to be functionally linked, with selection of highly invasive and metastatic cells leading to increased SSTC numbers. Collected data suggest a model in which SSTC are derived from a subset of cancer cells with increased resistance to apoptosis, and functional studies confirmed the induction of SSTC in such cells upon exposure to microenvironmental factors such as acidosis or hypoxia. In turn, several SASP factors from SSTC were found to act on neighboring cancer cells to increase their metastatic potential. Overall this thesis pinpoints a crucial role of SSTC for initiation of metastasis. The data harbor important translational implications, as, despite intensified screening and early detection efforts, almost half all human tumors are still diagnosed at advanced stages. Pharmacological senolysis in patients with increased cancer risk might allow to detect more cancers at earlier curative stages and thus greatly increase the prognosis of cancer patients.

Dissertation ist gesperrt bis 10. Februar 2027 !