Cancer Physiology (Aichi Cancer Center)

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CONTACT

Email	msaoki◎aichi-cc.jp (Please send a message after replacing "◎" mark with "@" mark. )
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OUTLINE

The Division of Cancer Physiology investigates how cancer arises within the body, how it progresses to malignancy and metastasis, and how cancer affects the host organism as a whole. Cancer develops through the accumulation of genetic abnormalities in the cells that constitute our bodies. Using genetically engineered mouse models in which cancers arise spontaneously, we focus on three key areas: (1) the tumor microenvironment, which includes not only cancer cells but also surrounding normal cells; (2) the molecular mechanisms of cancer metastasis; and (3) cancer cachexia, a condition frequently observed in cancer patients that is characterized by body weight loss accompanied by skeletal muscle wasting. Through these approaches, we aim to elucidate the mechanisms underlying cancer initiation, malignant progression, and metastasis, and to understand their systemic impact on the body.

RESEARCH PROJECTS

1) Elucidating the Role of the Tumor Microenvironment in Cancer Initiation and Malignant Progression

We investigate the roles of signaling pathways associated with the tumor microenvironment using multiple genetically engineered mouse models, including ApcΔ716 mice, which develop benign intestinal adenomas at early stages; Apc/Smad4 mice, which develop locally invasive adenocarcinomas; and mouse models of desmoid tumors, whose development is associated with activation of the Wnt signaling pathway.

Synthetic Lethality Between APC Mutation and Loss of MyD88 Function in Colorectal Cancer Cells

MyD88 functions as a critical adaptor protein in signaling pathways downstream of the IL-1 receptor and Toll-like receptors. Inducible knockout (KO) of MyD88 in intestinal epithelial cells of ApcΔ716 mice resulted in marked suppression of tumor formation, accompanied by reduced tumor cell proliferation and increased cell death. Mechanistically, the JNK–mTORC1, NF-κB, and Wnt signaling pathways were strongly suppressed in tumor cells. While MyD88 KO had minimal effects on normal intestinal organoids derived from ApcΔ716 mice, it induced cell death in tumor-derived organoids. Furthermore, suppression of MyD88 also induced cell death in human colorectal cancer cell lines harboring APC mutations. These findings demonstrate a synthetic lethal interaction between APC mutation and loss of MyD88 function, suggesting that inhibition of the MyD88 pathway may represent a potential therapeutic strategy for APC-mutant colorectal cancer (Kajino-Samakoto et al., Oncogene, 2021).

TGF-β Signaling Promotes Desmoid Tumor Formation via CSRP2 Expression

Desmoid tumors are rare mesenchymal soft tissue tumors characterized by aggressive local invasiveness. Although mutations in the CTNNB1 (β-catenin) gene are found in most desmoid tumors, their pathogenesis has remained poorly understood, and reliable mouse models have been lacking. We established a novel mouse model by locally administering tamoxifen subcutaneously to Pdgfra-CreERT2/Ctnnb1^flox(ex3) mice, which resulted in the formation of fibrous tumors histologically resembling human desmoid tumors. These tumors exhibited activation of the TGF-β signaling pathway, and introduction of Smad4 KO significantly suppressed tumor growth. Comparative proteomic analyses revealed that Smad4 KO reduced levels of Cysteine- and Glycine-Rich Protein 2 (CSRP2) in desmoid tumors. Treatment of desmoid tumor cell lines with TGF-β receptor inhibitors decreased CSRP2 expression, and CSRP2 KO suppressed cell proliferation, indicating that CSRP2 functions downstream of TGF-β signaling and may represent a therapeutic target for desmoid tumors (Li et al., Cancer Science, 2024).

2) Elucidation of Molecular Mechanisms of Metastasis and Identification of Preventive and Therapeutic Targets

The prognosis of metastatic colorectal cancer remains poor, highlighting the urgent need for novel therapeutic strategies. Accumulating evidence suggests that cancer stem cells and their plasticity contribute to intratumoral heterogeneity and play critical roles in therapeutic resistance, recurrence, and metastasis. However, the mechanisms regulating stemness in colorectal cancer remain largely unknown.

Maintenance of Cancer Stemness and Metastatic Capacity in Colorectal Cancer Using a Novel Metastatic Mouse Model

We successfully established a metastatic colorectal cancer mouse model (CKPS mice) by sporadically introducing mutations in four colorectal cancer–associated genes (Ctnnb1, Kras, Tp53, and Smad4) into intestinal epithelial cells. In this model, 100% of mice develop invasive adenocarcinomas, and 23% develop liver metastases. Gene expression analyses of intestinal tumors from CKPS mice revealed significantly elevated expression of the colorectal cancer stem cell markers PROM1 (CD133) and ALCAM (CD166) compared with normal colon tissue and non-metastatic colorectal cancers. Functional analyses using spheroid cultures and splenic injection–based liver metastasis models demonstrated that ALCAM and PROM1 are essential for maintaining stemness and metastatic capacity of CKPS-derived colorectal cancer cells. Further signaling pathway analyses revealed that ALCAM and PROM1 expression is positively regulated by the cAMP/PKA/CREB pathway and negatively regulated by the TGF-β/SMAD4 pathway. Inhibition of the cAMP/PKA/CREB pathway suppressed both stemness and metastatic potential of CKPS cells (Fujishita et al., Cancer Research, 2022).

3) Pathophysiological Analysis of Cancer Cachexia and Establishment of a Basis for Therapeutic Strategies

Cancer cachexia is a malnutrition syndrome driven by systemic inflammation and characterized by body weight loss, skeletal muscle atrophy, and anorexia. Approximately 80% of patients with advanced cancer develop cachexia, and it is estimated to be the direct cause of death in about 20% of cancer patients. Despite its clinical significance, early diagnostic methods and standard treatments have not yet been established.

Identification of Systemic Metabolic Dysregulation Associated with Cancer Cachexia Using Multi-Omics Analyses

To characterize systemic metabolic abnormalities associated with cancer cachexia, we performed omics analyses using multiple cancer mouse models that develop cachexia of varying severity, as well as a simple starvation model. Quantitative metabolomic analyses of skeletal muscle and liver revealed marked alterations in metabolites involved in NAD metabolism and one-carbon metabolism, which correlated with cachexia severity and were particularly pronounced in the liver. Quantitative proteomic analyses further demonstrated that hepatic levels of highly abundant enzymes related to vitamin B3 (NAD-related) and vitamin B6 metabolism decreased in proportion to cachexia severity. In the livers of cachectic mice, excessive expression of acute-phase proteins was observed, accompanied by increased levels of proteins associated with ribosomes, endoplasmic reticulum, and Golgi apparatus involved in protein synthesis and secretion, while liver-specific metabolic enzymes were markedly reduced. Importantly, these metabolic alterations involving NAD pathways were partially reflected not only in cachectic mouse models but also in blood samples from patients with gastric cancer cachexia. Changes in circulating metabolite levels correlated with the Glasgow Prognostic Score, a clinical indicator of cachexia severity (Kojima et al., Nature Communications, 2023).

BIBLIOGRAPHY