Abstract Cancer is often associated with reduced levels of certain nuclear envelope (NE) proteins, which contributes to irregularly shaped nuclei or nuclear dysmorphia. Nuclear dysmorphia can reflect compromised nuclear integrity and impaired DNA repair, which together can drive genomic instability and tumor development. Accordingly, expression levels of NE proteins—including LEM-domain proteins—are emerging as informative biomarkers for tumor detection, classification, and patient prognosis. Given that LEM2, an NE-associated LEM-domain protein, is altered in multiple cancers, we explored the effects of LEM2 depletion on phenotypic outcomes associated with cancer progression. Traditionally, the role of NE proteins in cancer phenotypes has been studied within the context of their canonical nuclear roles. However, hints from the literature suggest LEM2 contributes to the regulation of a physically connected organelle, the endoplasmic reticulum (ER). Despite the functional coupling and the physical continuity between the membranes that enclose the nucleus –the NE– and the ER, how changes originating in the nucleus influence ER organization and homeostasis remains poorly understood. Therefore, we examined whether disrupting LEM2 affects ER homeostasis—an important regulator of cancer progression. When ER homeostasis is disrupted, the unfolded protein response (UPR) pathway relays ER stress signals to the nucleus via transcriptional programs to alleviate ER stress and promote cell survival. Cancer cells often exploit the adaptive features of the UPR, and UPR components have emerged as promising biomarkers for predicting treatment response and prognosis. Here, we identify a novel mechanism of nucleus-to-ER communication in which loss of LEM2 triggers non-canonical activation of a specific branch of the UPR. Rather than responding to classic proteotoxic stress, the UPR activated by LEM2 depletion appears to arise from alterations in specific lipids. Our findings define a novel nucleus-to-ER signaling axis through which the NE modulates lipid-mediated UPR activity in the ER. Ongoing work aims to determine how this nucleus-to-ER pathway affects additional cancer phenotypes and to dissect how NE perturbations alter ER lipid homeostasis to activate the UPR. More broadly, uncovering the inter-organelle regulatory mechanisms of NE-ER communication provides a novel framework for gaining insight into tumor development. Citation Format: Natasha O. Saik, Maho Niwa, Katharine S. Ullman. A link between the nuclear envelope protein LEM2 and an endoplasmic reticulum stress signaling pathway provides new insight into features of tumor development 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 6004.
Saik et al. (Fri,) studied this question.