Abstract B045: The effect of metastasis-associated in colon cancer 1 (MACC1) on therapy-induced senescence and its impact on post-senescence-driven metastasis
Authors: Güllü Belma Nazli , Fan Dorothy N. Y. , Kobelt Dennis , Mokrizkij Margarita , Smith Janice , Schmitt Clemens A. , Stein Ulrike 
Published: January 2023

Abstract
Senescence is considered a safeguard program against cancer progression. However, recent studies revealed that these cells, reprogrammed in a senescence-associated fashion to express stemness transcripts, may occasionally re-enter the cell cycle, thereby executing their increased tumorigenicity. Although the effects of senescence, its associated secretome (SASP) and release from senescence on tumor progression have been elucidated before, the role of post-senescent cells in metastasis remains elusive. To enlighten the relationship between senescence, stemness, and metastasis, we employed a key bridging molecule between metastasis and cancer stemness, metastasis-associated in colon cancer 1 (MACC1). Numerous research groups have acquainted its importance as a metastasis inducer, prognostic, and predictive biomarker for more than 20 different tumor entities, including breast and colorectal cancer (CRC). We initially used CRC cell lines with genetically engineered MACC1 expression for our study. Senescence was induced with different chemotherapeutic agents such as 5-FU, mafosfamid (a cyclophosphamide analogue active in vitro), and doxorubicin. Cells with high MACC1 expression were more prone to senesce after treatment. These findings were further validated in CRC patient- and mouse-derived organoids. Across these models, we found MACC1 expression to increase therapy-induced senescence (TIS). Moreover, senescence induction was accompanied by increased MACC1 expression in conjunction with elevated expression of cancer stemness genes like CD44 and LGR5; this increase was more prominently detectable in MACC1 high-expressing cells. Furthermore, senescent cells were forced to exit from senescence through genetic manipulations of independent senescence-essential factors such as overexpression of JMJD2C, which demethylates the senescence-essential H3K9me3 histone mark. Post-senescent cells showed enhanced migration, colony formation, wound healing, proliferation, and increased cancer stemness-related gene expression, especially when compared to never-senescent cells in which we overexpressed JMJD2C prior to chemo-exposure. Our studies were complemented by in vivo work, which showed that metastasis-incapable CRC cells formed metastasis in the liver and lung after their release from senescence. We further used MACC1 inhibitors such as atorvastatin and fluvastatin to interfere with MACC1-induced TIS. The co-treatment of a MACC1 inhibitor with conventional chemotherapeutics reduced senescence entry in cells with high MACC1 expression. These data, consistent with our findings in primary patient material, uncover a hitherto unknown relationship between MACC1 and TIS. Furthermore, senescence release increases the tumorgenicity of the cells, which is more prominent in the cells with high MACC1 expression. In particular, we were able to reduce MACC1-induced senescence by using MACC1 inhibitors, aiming to reduce the senescence release-induced metastasis.
Citation Format: Belma Nazli Güllü, Dorothy N. Y. Fan, Dennis Kobelt, Margarita Mokrizkij, Janice Smith, Clemens A. Schmitt, Ulrike Stein. The effect of metastasis-associated in colon cancer 1 (MACC1) on therapy-induced senescence and its impact on post-senescence-driven metastasis [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr B045.