Abstract PR016: Early changes to the colon tumor microenvironment during benign-to- malignant transition

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Abstract Colorectal cancer (CRC) is now the first and second leading cause of cancer-related deaths in men and women under 50, respectively, upending prior predictions. While many risk factors have been identified, the etiology of early onset disease is poorly understood, and it is unclear why some benign polyps progress to CRC while most do not. The genetic drivers of colon tumor initiation and progression to malignancy are not sufficient to drive disease on their own, as evidenced by the near ubiquitous presence of oncogenic mutations within morphologically “normal” adult tissues like the colon. This raises several fundamental questions: 1) what are the pioneering molecular and cellular events underlying benign-to-malignant transition following oncogenic mutation? 2) Is this sequence of events predetermined by cancer genetics or are additional (micro)environmental stimuli necessary? 3) How does the benign-to-malignant transition reshape tumor clonal architecture and is this immunogenic? We have begun to address these questions using a combination of rare human colon polyps with evidence of early malignant transition and innovative new mouse models that enable control of stepwise colon cancer progression. These autochthonous models combine in vivo CRISPR-Cas9 and an inducible “split-Cre” system to decouple focal tumor initiation in the distal colon (via Apc knockout) from spatiotemporal control of secondary driver events of malignant progression (e.g., Kras G12D, Trp53 knockout) in rare cells of benign adenomas. We have validated the in vivo functionality of these models, generating early “intramucosal carcinoma” and “adenocarcinoma-in-adenoma”—physiologically relevant and elusive stages of human colon cancer development that have never been reliably captured in model systems to date. Comparing these tumors with spatial transcriptomic data from human specimens, we report distinct transcriptional programs of early progression, a unique stromal reaction associated with early progression, and restructuring of glandular architecture and the stem cell niche in early carcinoma. By delineating the earliest events underlying cancer progression, this work promises to inform new strategies for early detection and prevention. We anticipate that the models will also be particularly valuable in functionally interrogating host and environmental factors that impact risk of early onset cancer. Citation Format: Peter M.K. Westcott, Yihan Qin, Daniel Zhang, Nikita Persaud, Zakeria Aminzada, Nischal Bhandari, Colin McLaughlin, William Rideout III, Santiago Naranjo, Song Han, Rodrigo Romero, Claire Regan, Jonathan Preall, Semir Beyaz, Tyler Jacks, Zhen Zhao, Sepideh Gholami. Early changes to the colon tumor microenvironment during benign-to- malignant transition [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr PR016.

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