Abstract C074: Influence of Cell Death and Stress on the Tumor Microenvironment and EMT in Pancreatic Ductal Adenocarcinoma Through Single Cell and Spatial Transcriptomics

Abstract Pancreatic cancer remains one of the most deadly cancers, with over 450, 000 fatalities in 2022 alone. The most lethal variation of this cancer is Pancreatic Ductal Adenocarcinoma (PDAC), with a 5-year survival rate of under 10%. Combination chemotherapy has provided major advances in this disease but it remains challenging for many reasons including the immunosuppressive nature of the tumor microenvironment (TME). PDAC has a highly desmoplastic microenvironment that suppresses antitumor immunity and promotes tumor cell invasion, metastasis, and resistance through epithelial to mesenchymal transition (EMT) of cancer cells. Cancer cells can undergo various forms of cell death, notably apoptosis, necrosis, autophagy, pyroptosis, and ferroptosis. These mechanisms are triggered by different cellular stressors and shape the microenvironment. Through the use of 15 Visium spatial transcriptomics samples from publicly available primary PDAC tumors and paired single-cell RNA (scRNA) data, we aim to understand how cell stress and cell death shape the tumor microenvironment (TME) and epithelial-mesenchymal transition (EMT). By leveraging information from known pathways in literature, we will identify cellular programs related to stress, death, and EMT. We will explore intracellular correlations within single-cell data and extracellular interactions within the TME using spatial data to uncover how different forms of cell death and stress signatures influence the TME and EMT spectrum. The initial phase involves identifying the types of stress that lead to various forms of cell death intracellularly and validating these gene signatures. Subsequently, we will apply these validated signatures to the spatial data to correlate each score and search for significant overlapping programs. This will extend beyond stress and death, incorporating TME signatures corresponding to different cell types and the EMT spectrum. By understanding the signals that promote the death of various cell populations, we aim to identify combination treatments that target both ends of the EMT spectrum. Additionally, this research will provide insights into the inflammatory impact of cell death on the TME. Our approach aims to inform the development of therapies that disrupt resistance mechanisms, ultimately improving treatment outcomes for patients with PDAC. This research can potentially reveal new therapeutic targets and strategies, enhancing our ability to combat this deadly disease. Citation Format: Rahul Bansal, Izabella Zamora, Samuel Wright, Nir Hacohen, Arnav Mehta. Influence of Cell Death and Stress on the Tumor Microenvironment and EMT in Pancreatic Ductal Adenocarcinoma Through Single Cell and Spatial Transcriptomics abstract. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84 (17 Suppl₂): Abstract nr C074.