Cellular Senescence in Tumor Suppression and Tissue Pathology

The cellular senescence program is a tumor suppressive process controlled by p53 of particular interest to our group. Senescence is a stable form of proliferative arrest that acts as a potent barrier to cancer development and may contribute to various age-related diseases.

Initially defined by the phenotype of cultured fibroblasts undergoing replicative exhaustion, senescence can be triggered in many cell types by a range of cellular stresses. Our interest in the process originated from the observation that oncogenic Ras proteins could trigger senescence in primary cells through Rb and p53 dependent mechanisms, thereby preventing oncogenic transformation  (1). Accordingly, we proposed that “oncogene-induced senescence” acts as a cellular failsafe mechanism to suppress tumorigenesis, a hypothesis that is now supported by numerous animal and human studies. 

Our recent efforts in studying senescence have explored mechanisms whereby oncogenic signaling can trigger a stable cell cycle arrest using a combination of genetics, cell biology, and biochemical approaches. We identified Jarid1a/b-mediated H3K4 demethylation as a contributor to silencing of retinoblastoma targeting genes in senescent cells  (2). We also identified the transcription factor E2F7 as an important senescence regulator that provides a novel link between the p53 and Rb pathways (Figure 1)  (3). Concomitant suppression of E2F7 and Rb by RNAi cooperate to bypass oncogenic Ras induced senescence and transformation.

In addition to cell autonomous aspects of the program that produce a stable cell cycle arrest, senescent cells secrete a set of inflammatory cytokines and other factors as part of a process termed the “senescence-associated secretory phenotype,” or SASP. Using in vivo models of hepatocellular carcinoma, we found that induction of senescence in liver tumor cells via restoration of p53 can trigger the clearance of cancer cells by cells of the innate immune system  (4). In addition, we showed (Figure 2) that ablation of p53 and its associated senescence program in hepatic stellate cells in the context of chronic liver damage promotes fibrosis and cirrhosis as well as transformation of hepatocytes into hepatocellular carcinoma (5),(6). p53-mediated senescence in these stromal cells protects against malignancy by secreting factors that polarize macrophages toward an M1 state, which renders them capable of attacking senescent tumor cells, while p53-deficiency in stellate cells results in a pro-inflammatory M2 macrophage polarization that further enhances tumorigenesis. These studies underscore non-cell autonomous roles for p53 that function to protect against malignancy. Efforts are ongoing to mechanistically dissect these and other tumor-host interactions further.

Figure 2. p53 signaling through SASP modulates macrophage function. --  A) and B) Cytokines and chemokines regulated by p53 (in blue) in senescent (S) hepatic stellate cells, compared with proliferating (P) cells. C) Macrophages (red) specifically target senescent hepatic stellate cells (green) (Lujambio et al., Cell, 2013).

  1. Serrano, M., Lin, A.W., McCurrach, M.E., Beach, D., and Lowe, S.W. (1997). Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell 88, 593-602.

  2. Chicas, A., Kapoor, A., Wang, X., Aksoy, O., Evertts, A.G., Zhang, M.Q., Garcia, B.A., Bernstein, E., and Lowe, S.W. (2012). H3K4 demethylation by Jarid1a and Jarid1b contributes to retinoblastoma-mediated gene silencing during cellular senescence. Proc Natl Acad Sci U S A.

  3. Aksoy, O., Chicas, A., Zeng, T., Zhao, Z., McCurrach, M., Wang, X., and Lowe, S.W. (2012). The atypical E2F family member E2F7 couples the p53 and RB pathways during cellular senescence. Genes Dev 26, 1546-1557.

  4. Davare, M.A., Saborowski, A., Eide, C.A., Tognon, C., Smith, R.L., Elferich, J., Agarwal, A., Tyner, J.W., Shinde, U.P., Lowe, S.W., et al. (2013). Foretinib is a potent inhibitor of oncogenic ROS1 fusion proteins. Proc Natl Acad Sci U S A 110, 19519-19524.

  5. Krizhanovsky, V., Yon, M., Dickins, R.A., Hearn, S., Simon, J., Miething, C., Yee, H., Zender, L., and Lowe, S.W. (2008). Senescence of activated stellate cells limits liver fibrosis. Cell 134, 657-667.

  6. Lujambio, A., Akkari, L., Simon, J., Grace, D., Tschaharganeh, D.F., Bolden, J.E., Zhao, Z., Thapar, V., Joyce, J.A., Krizhanovsky, V., et al. (2013). Non-Cell-Autonomous Tumor Suppression by p53. Cell 153, 449-460.