Targeting Cellular Senescence in Cancer

Despite intensive efforts to improve early cancer detection, to date 30% of all solid tumors
are still diagnosed at a metastasized and incurable stage. Molecular mechanisms underlying
early metastasis are poorly understood, and thus far there are no strategies to suppress it.
Here, using high-plex spatial protein profiling of human and murine tumours as well as
functional studies in mouse models, we show that intratumoral microenvironmental stress
factors induce senescence of apoptosis resistant tumor cells, resulting in a tumor-interlacing
senescence matrix. Single cell RNA sequencing analyses revealed that matrix building cells,
designated as stress-induced senescent tumor cells (SITC), harbour a distinct secretory
phenotype, which fails to induce a full paracrine senescence phenotype in adjacent cancer
cells but instead induces a hybrid senescence/invasion phenotype characterized by
intermediate p16 levels and the upregulation of gene sets known to increase invasion and
metastasis. Frequency of SITC in human therapy-naïve tumours was found to correlate with
their metastatic stage at diagnosis and pharmacological or genetic depletion of SITC
markedly reduced metastasis in orthotopic mouse models of colorectal cancer and
intrahepatic cholangiocarcinoma. Our data harbours important translational potential, as
recurrent pharmacological senolytic or senomorphic treatments hold the promise to eradicate
SITC from occult tumors and this way prevent their early metastatic spread, allowing to
diagnose more cancers at earlier and potentially curative stages. Clinical trials to address
this hypothesis are warranted.