Abstract 6419: Stress-induced intratumoral senescence matrix shifts cancer evolution towards metastasis

Abstract 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. Citation Format: Omelyan Trompak, Svenja A. Schütte, Jorge Abreu Macedo, Sophia Scheuermann, Zexi Hu, Igor Minia, Artür Manukyan, Thales Kronenberger, Marcello Zago, Rosanna Krebs, Alice Nuernbergk, Tae-Won Kang, Carlotta Schieler, Liudmyla Taranets, Angel M. Cuesta, Michael Forster, Kristin Bieber, Wolfgang Albrecht, Elke Rist, Can Yurttas, Daniel Dauch, Bettina Weigelin, Bence Sipos, Thomas Longerich, Stephan Singer, Markus W. Löffler, Manfred Claassen, Florian Wimmers, Markus Landthaler, Alfred Königsrainer, Saskia Biskup, Stefan Laufer, Christian M. Seitz, Lars Zender. Stress-induced intratumoral senescence matrix shifts cancer evolution towards metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6419.