Akt regulates critical cellular processes including cell survival and proliferation, glucose metabolism, cell migration, cancer progression and metastasis through phosphorylation of a variety of downstream targets. The Akt pathway is one of the most prevalently hyperactivated signaling pathways in human cancer, thus, research deciphering molecular mechanisms which underlie the aberrant Akt activation has received enormous attention. The PI3K-dependent Akt serine/threonine phosphorylation by PDK1 and mTORC2 has long been thought to be the primary mechanism accounting for Akt activation. However, this regulation alone does not sufficiently explain how Akt hyperactivation can occur in tumors with normal levels of PI3K/PTEN activity. Mounting evidence demonstrates that aberrant Akt activation can be attributed to other posttranslational modifications, which include tyrosine phosphorylation, O-GlcNAcylation, as well as lysine modifications: ubiquitination, SUMOylation and acetylation. Among them, K63-linked ubiquitination has been shown to be a critical step for Akt signal activation by facilitating its membrane recruitment. Deficiency of E3 ligases responsible for growth factor-induced Akt activation leads to tumor suppression. Therefore, a comprehensive understanding of posttranslational modifications in Akt regulation will offer novel strategies for cancer therapy.

Background Type II diabetes mellitus (DM2) is a significant risk factor for cancers, including breast cancer. However, a proper diabetic breast cancer mouse model is not well‐established for treatment strategy design. Additionally, the precise diabetic signaling pathways that regulate cancer growth remain unresolved. In the present study, we established a suitable mouse model and demonstrated the pathogenic role of diabetes on breast cancer progression. Methods We successfully generated a transgenic mouse model of human epidermal growth factor receptor 2 positive (Her2+ or ERBB2) breast cancer with DM2 by crossing leptin receptor mutant (Leprdb/+) mice with MMTV‐ErbB2/neu) mice. The mouse models were administrated with antidiabetic drugs to assess the impacts of controlling DM2 in affecting tumor growth. Magnetic resonance spectroscopic imaging was employed to analyze the tumor metabolism. Results Treatment with metformin/rosiglitazone in MMTV‐ErbB2/Leprdb/db mouse model reduced serum insulin levels, prolonged overall survival, decreased cumulative tumor incidence, and inhibited tumor progression. Anti‐insulin resistance medications also inhibited glycolytic metabolism in tumors in vivo as indicated by the reduced metabolic flux of hyperpolarized 13C pyruvate‐to‐lactate reaction. The tumor cells from MMTV‐ErbB2/Leprdb/db transgenic mice treated with metformin had reprogrammed metabolism by reducing levels of both oxygen consumption and lactate production. Metformin decreased the expression of Myc and pyruvate kinase isozyme 2 (PKM2), leading to metabolism reprogramming. Moreover, metformin attenuated the mTOR/AKT signaling pathway and altered adipokine profiles. Conclusions MMTV‐ErbB2/Leprdb/db mouse model was able to recapitulate diabetic HER2+ human breast cancer. Additionally, our results defined the signaling pathways deregulated in HER2+ breast cancer under diabetic condition, which can be intervened by anti‐insulin resistance therapy.

No abstract

In recent years, checkpoint blockade has been used successfully to treat many cancer types including melanoma, non-small cell lung, and colorectal cancers. In stark contrast, the response to these new immunotherapeutics has been poor in patients with pancreatic ductal adenocarcinoma (PDAC), the most common and lethal type of pancreatic cancer. Thus, PDAC is considered a cold tumor for immunotherapy and the mechanism underlying this resistance is poorly understood. Insulin-like growth factor binding protein-2 (IGFBP2), a secreted cytokine, is elevated in the serum, pancreatic juice, and PDAC tissues in many pancreatic cancer patients, and we demonstrated that high levels associate to reduced overall patient survival and promote the immunosuppressive M2 tumor-associated macrophage phenotype in the tumor microenvironment (TME). We recently identified IGFBP2 as a key oncogenic signaling molecule for PDAC metastasis and epithelial-to-mesenchymal transition. Our preliminary microarray analysis showed that major histocompatibility complex class II antigen (MHC class II) genes were significantly downregulated in AsPC-1 pancreatic cancer cells overexpressing IGFBP2. MHC class II molecules are constitutively expressed in antigen-presenting cells (APCs) such as dendritic and Langerhans cells, macrophages, and B lymphocytes. In PDAC, increased MHC class II expression correlates to a higher histologic grade of differentiation. Also, CD4+ T lymphocyte numbers in PDAC tissues positively correlate to MHC class II expression levels. We envision that high IGFBP2 represses MHC class II gene expression in the tumor-associated APCs, resulting in failure of recruitment and activation of CD4+ lymphocytes, augmenting the immunosuppressive TME. The mechanism whereby IGFBP2 regulates MHC class II gene expression, however, is unknown. IGFBP2 was reported to physically interact with Pim-1-associated protein-1 (PAP-1)-associated protin-1 (PAPA-1) in the nucleus. PAPA-1 (or INO80B) is a key component in the ATP-dependent INO80 chromatin-remodeling complex. A recent study shows that INO80 is required for super-enhancer-mediated oncogenic transcription and tumor growth in melanoma. Interestingly, the MHC class II genes HLA-DR and HLA-DQ were found to be regulated by a super-enhancer mediated mechanism in autoimmune disease. We hypothesized that tumor-secreted IGFBP2 directly regulates INO80 function and inhibits the MHC class II expression in APCs in the TME. Our preliminary data show that exogenous IGFBP2 translocates into the cell nucleus within hours, and co-immunoprecipitation confirmed that IGFBP2 interacts with INO80B in vitro. Furthermore, MHC Class II expression was downregulated by IGFBP2 in the murine DC 2.4 dendritic cell line and in mouse bone marrow-derived dendritic cells by RT-PCR and flow cytometry. Our data suggest that PDAC IGFBP2 levels might predict checkpoint blockade therapy readiness, and importantly, serve as a target mechanism for enabling immunotherapy effectiveness. Citation Format: Ping-Chieh Chou, Liang Liu, Elizabeth Forbes, Ashley Ballard, Tao Li, Wei Zhang. IGFBP2 reprograms pancreatic cancer immune surveillance at epitranscriptome levels [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr B98.

No abstract