Abstract 6340: Pancreatic cancer specific <i>Bmal1</i>-floxed mice reduced malignant potentials and prolonged survival

Abstract Introduction: Dysregulation of clock genes has been reported in pancreatic ductal adenocarcinoma (PDAC), but the effects of the dysregulation on circadian rhythm, PDAC carcinogenesis, progression and prognosis remain unclear. To investigate the effects of dysfunctional Bmal1, a major clock gene, we compared KPPC (LSL-KrasG12D/+; Trp53flox/flox; Pdx-1cre/+) and KPPBC (LSL-KrasG12D/+; Trp53flox/flox; Bmal1flox/flox; Pdx-1cre/+) transgenic mice with PDAC. Methods: Six-week-old KPPC and KPPBC mice were housed in wheel cages, and the circadian rhythms were measured until the humane endpoint. Tumor status and plasma cytokine levels were determined using histopathological analysis and cytokine array, respectively. Results: KPPBC mice retained wheel activity at the terminal stage and prolonged the survival rate compared to KPPC mice. The pancreatic tumor volume of KPPBC mice was smaller than that of KPPC mice. The proliferative Ki67 index and invasive frequency of PDAC in KPPBC mice were lower than in KPPC mice. Local MPO+ tumor-associated neutrophils (TANs) and arginase-1+ M2-like tumor-associated macrophages (TAMs) mice decreased in KPPBC mice compared to KPPC mice, whereas iNOS+ M1-like TAMs and CD8+lymphocytes increased in KPPBC mice compared to KPPC mice. Indeed, gastrocnemius muscle atrophy with cachexia was observed in both mice groups at the terminal stage, but average area of the gastrocnemiusmuscle in KPPBC mice was larger than in KPPC mice. Plasma levels of IGF-I and IGF-II in KPPBC mice were higher than in KPPC mice. The proliferation of PDAC cell lines with Bmal1-deficient was slower than that of PDAC cell lines with wild type of Bmal1 in vitro. Conclusions: These results suggest that inhibition of the proliferative potential of Bmal1-floxed PDAC could result from the direct effect of Bmal1 deficiency and alteration of tumor microenvironment. Meanwhile, the delay of gastrocnemius muscle atrophy in KPPBC mice may be due to an increase in cytokines such as IGF-I and IGF-II. Citation Format: Jinsuk Kim, Yukino Oshima, Ichie Kajiwara, Tomoaki Itaya, Tomoya Kuramochi, kaori saito, Taira Wada, Takahiro J. Nakamura, Shigeki Shimba, Hideaki Ijichi, Makoto Sano, Takahiro Suzuki. Pancreatic cancer specific Bmal1-floxed mice reduced malignant potentials and prolonged survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6340.