[A3 Foresight Program]

Based on an agreement among JSPS, National Research Foundation of Korea(NRF) and National Natural Science Foundation of China(NSFC), this program supports joint research conducted by researchers of Japan, China and Korea. The three countries(A3) work as consortium in advancing leading-edge research with an aim to establishing a top- level research hub in Asia

Prof. Naoko Ohtani, Osaka Metropolitan University

Title: Senescent CAF-derived secretome in the MASLD-associated liver tumor microenvironment

Abstract:

Naoko Ohtani^*

Department of Pathophysiology, Graduate School of Medicine, Osaka Metropolitan University

Metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH) have emerged as major contributors to hepatocellular carcinoma (HCC). However, the precise mechanisms underlying liver cancer development in these conditions remain unclear. We previously revealed that obesity-induced deoxycholic acid (DCA), a gut microbial metabolite, triggers a senescence-associated secretory phenotype (SASP) in hepatic stellate cells (HSCs), a secretome that senescent cells secrete a variety of inflammatory cytokines, chemokines, proteases, and so on. In addition, lipoteichoic acid (LTA), a gram-positive gut microbial component, enhances SASP via Toll-like receptor 2 activation. Furthermore, IL-33, which is highly expressed in liver tumor regions, particularly within senescent HSCs, plays a crucial role in HCC development in an IL-1β-dependent manner. We found that the SASP factors, including IL-33 and IL-1β, were released via membrane pores formed by the gasdermin D N-terminal domain, which is facilitated by LTA. The released IL-33 suppresses antitumor immunity by activating ST2-positive Treg cells, thereby contributing to the progression of steatosis-associated HCC. We further characterized HSCs as cancer-associated fibroblasts (CAFs) using Flex single-cell transcriptome analysis of human HCC tissues, along with spatial transcriptome analysis showing the localization of each HSC type. We identified a SASP factor from these senescent HSCs that correlated with the HCC patients’ poor prognosis, highlighting their potential as biomarkers for steatotic HCC progression.

Prof. Akiko Takahashi, Japanese Foundation for Cancer Research

Title: Therapeutic Potential of Targeting Metabolic Dysregulation in Senescent Cells

Abstract:

Tze Mun Loo¹, Xiangyu Zhou^1,2, Jianghao Qian^1,2, Ki-seok Lee¹, Yoko Tanaka¹, Sho Sugawara¹, Shota Yamauchi¹, Akiko Takahashi^1,2*

¹Division of Cellular Senescence, Cancer Institute, Japanese Foundation for Cancer Research, Japan

²Laboratory of Cellular Senescence Biology, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Japan

Senescent stromal cells secrete many inflammatory and pro-proliferative factors via the senescence-associated secretory phenotype (SASP), promoting the development and progression of cancer. Senescent cells exhibit resistance to ferroptosis, a form of iron-dependent cell death; however, the underlying mechanisms remain unclear. Here, we discovered that lysosomal function was crucial for lipid peroxidation and ferroptosis induction by cystine deprivation. In senescent cells, the expression of component of V-ATPase was downregulated, leading to lysosomal dysfunction and resistance to lipid peroxidation and ferroptosis. V-ATPase activation restored ferroptosis sensitivity in senescent cells and pancreatic cancer cells. Furthermore, the induction of ferroptosis sensitivity prevented pancreatic cancer development in xenograft and Kras mutant mouse models. In addition, we recently investigated the molecular mechanism of paraptosis-like cell death in senescent cells. Our findings highlight the therapeutic potential of targeting metabolic dysregulation in senescent cells for cancer treatment.