Santhilal Subhash

IER3: exploring its dual function as an oncogene and tumor suppressor

Abstract The IER3 gene has a complex role in cancer biology, acting either as a tumor suppressor or an oncogene, depending on the cancer type. This duality underscores the complexity and importance of molecular pathways in modulating cancer behavior. Despite its significance in cancer development, there is a dearth of studies elucidating the exact mechanisms underlying IER3’s involvement in modulating cancer behavior. Here, utilizing cervical carcinoma and neuroblastoma (NB) cell lines as model systems we characterized the pathways that mediate the functional switch between the oncogenic and tumor suppressor roles of IER3. In HeLa cells, IER3 expression promotes an oncogenic program that includes immediate early response pathway genes such as EGR2, FOS, and JUN. However, in NB cells, IER3 suppresses the EGR2-dependent oncogenic program. This differential regulation of EGR2 by IER3 involves epigenetic modulation of the EGR2 promoter. IER3 dependent tumor suppressor pathway in NB cells relies on ADAM19 gene. Thus, our findings uncover the molecular pathways that dictate the context-dependent roles of IER3 in cancer, providing insights into its dual functionality in different cancer types.

Ancestrally Diverse Autologous Patient-Derived Organoid–Immune Cell Coculture Platform for Addressing Immunotherapeutic Outcome Disparities in High-Grade Endometrial Cancer

Abstract High-grade endometrial cancers (HGEC) disproportionately affect women of African ancestry and often resist currently available immunotherapies. Defining the mechanisms driving this resistance is impeded by a lack of preclinical models that preserve ancestral diversity and patient-matched tumor–immune interactions without confounding alloreactivity. To address this gap, we established a biobank of 85 endometrial cancer patient-derived organoids (PDO) from a diverse cohort, enriched for HGEC PDOs from African American patients, and paired these with autologous immune cells to develop a patient-specific PDO–immune cell coculture platform with real-time live-imaging readouts. Using this system, we found that HGECs evade immune surveillance through pronounced suppression of major histocompatibility complex (MHC) class I and II antigen presentation pathways relative to their matched normal counterparts. Restoring antigen presentation, either by IFNγ stimulation or epigenetic reprogramming via enhancer of zeste homolog 2 inhibition, rescued MHC expression and sensitized HGEC PDOs to autologous T cell–mediated cytotoxicity. Extending the platform to NK cells revealed heightened killing of low–MHC-I PDOs. Consistent with clinical observations, mismatch repair (MMR)-deficient HGEC PDOs exhibited stronger immune engagement than their MMR-proficient counterparts. Finally, this platform enabled evaluation of the safety and efficacy of emerging immunotherapies, including protease-activatable bispecific T-cell engagers and EGFR-targeted chimeric antigen receptor T cells. Together, this sustainable, scalable, ancestrally diverse autologous PDO–immune cell coculture platform offers a robust resource for dissecting immune evasion mechanisms and accelerating the development of new immunotherapies to address disparities in endometrial cancer outcomes. Significance: The efficacy of immunotherapy for HGECs remains limited, partly because current preclinical models poorly capture tumor heterogeneity and patient-specific immune microenvironment. These cancers disproportionately affect women of African ancestry, yet most studies rely on European ancestry samples. We developed an autologous PDO and immune cell coculture platform from patients of diverse ancestries. This system enables patient-level analysis of tumor–immune interactions to support development and testing of novel immunotherapeutic strategies.