The Characteristics of Senescent Tumor Cells in Colorectal Cancer

Abstract

Cellular senescence, traditionally defined as a state of permanent cell cycle arrest, has long been considered a protective mechanism against cancer progression. However, recent research has unveiled a more complex relationship between senescence and cancer. This dissertation aimed to identify novel markers for visualizing and targeting senescent tumor cells in colorectal cancer (CRC). The dissertation also revealed a fascinating aspect of CRC cell behavior: a gradual evolution from well-formed glandular structures to collective invasion, culminating in the development of cancer cell budding at the invasive front. This evolutionary process was accompanied by cancer cell senescence, challenging conventional knowledge about the defensive role of senescence against cancer progression. Trajectory and immunohistochemistry analyses uncovered two distinct types of senescent tumor cells, designated as type I and type II. These two types played different roles in the progression of CRC due to differences in their gene expression profiles. Type I senescent tumor cells (p16INK4A+/LAMC2-/MMP7-) were primarily found in the collective invasion region of CRC. In contrast, type II senescent tumor cells (p16INK4A+/LAMC2+/MMP7+), representing the final evolutionary stage of cancer cells, were predominantly located in the partial-EMT region. These type II cells were strongly associated with local invasion and lymph node metastasis in CRC, potentially leading to a worse prognosis for patients. Overall, the dissertation sheds new light on the complex interplay between cellular senescence and cancer progression in the context of CRC. It highlights the diverse roles that senescent tumor cells can play in the tumor microenvironment. Key words: Cellular senescence, Senescent tumor cells, cancer evolution, senescence- associated secretory phenotype, single-cell RNA-sequencing