Abstract Endometrial cancer (EC) is the most common gynecological malignancy, and metastatic or recurrent EC remains largely incurable with current therapies. Emerging evidence shows that alterations in the tumor microenvironment play a critical role in driving therapeutic resistance and poor outcomes in EC. Here, we investigated the molecular pathways that drive aggressive tumor behavior in EC using genetically engineered mouse models. Uterine specific conditional Pten and Pten/Mig-6 knockout mice were generated using the Pgrcre system. Quantitative proteomic profiling of uterine tissues using the ASTRAL platform identified 862 differentially expressed proteins (DEPs) (fold change ±2, FDR 0.05) between double mutant (Mig-6d/dPtend/d) and single mutant (Ptend/d) uteri at 4-months of age. Ingenuity pathway analysis revealed significant enrichment of fibrosis-related signaling, collagen organization, cellular invasion, and proliferative pathways. Consistent with these results, immunohistochemistry demonstrated increased expression of collagen alpha-1(I) chain, MMP3, and phospho-ERK1/2 in double mutant uteri compared to single mutants, correlating with enhanced fibrotic remodeling. Masson’s trichrome staining further confirmed extensive collagen deposition and fibrosis accompanying tumor progression in the double mutant mice. Collectively, these findings suggest that loss of Mig-6 in a Pten-deficient uterus activates ERK signaling and MMP-mediated extracellular matrix remodeling, promoting a fibrotic and invasive tumor microenvironment that contributes to metastasis and therapeutic resistance in endometrial cancer. This work was supported by NCI R01CA264944. Citation Format: Shamsun Nahar, Kyeong A So, Keun Chen Kim, Jung Yoon Yoo, Jiyoung Yu, Kyunggon Kim, Eunhee M Jeong, Da-Hye Kang, Tae Hoon Kim, Jae-Wook Jeong. Mig-6 deficiency accelerates fibrotic tumor microenvironment formation in Pten-deficient endometrial tumors abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 764.
Nahar et al. (Fri,) studied this question.