PROJECT SUMMARY/ABSTRACT: This application is being submitted in response to the Notice of Special Interest (NOSI) identified as NOT-CA_21-100. It consists of a research and career development plan for the NCI’s Early-stage Surgeon Scientist Program (ESSP) pertaining to the rapid recurrence of pancreatic cancer after surgical resection. The objective of this proposal is to understand the origins of pancreatic cancer that recurs within six months of surgical resection in the liver, a devastating phenomenon that is poorly understood, while advancing the skills, methodology, and competencies necessary for independence as a surgeon-scientist. The first aim is based on a novel, immune competent mouse model that recapitulates rapid recurrence. It is designed to deeply characterize the biologic underpinnings of this phenomenon with single-cell RNA sequencing of tissues in pre-, intra-, and post-metastatic compartments that are not possible to obtain in humans followed by robust histologic contexture and analysis of the primary and metastatic tumors and their microenvironments. We will investigate the mechanisms by which surgical intervention itself may disseminate or exacerbate metastases. The second aim will evaluate in parallel tissues and derived cell lines from patients who experienced a rapid recurrence after surgery, comparing these to the tumors and cell lines from patients who did not recur for at least eighteen months. The objective of this aim is to characterize the immune and microenvironmental contexture of these tissues and the behavior of the cell lines to understand translational applications and generate additional lines of inquiry over the period of the proposed study. Both aims are geared towards elucidating how cancer cells, the tumor itself, and systemic factors contribute to mechanisms of rapid recurrence. Additional studies will be designed as the subject of the grants, abstracts, and papers outlined in the curriculum as a part of the ESSP. Throughout this proposal, a robust yet attainable curriculum has been structured to improve experimental design and promote mastery of techniques and methodologies that will be broadly applicable to a successful transition to independence as a surgeon scientist. I have established an excellent mentoring team in my primary mentor Dr. Rosalie Sears and my co-mentors Dr. Jonathan Brody and Dr. Brett Sheppard, all leaders within our cancer center, pancreatic cancer biology, and surgical science. Additional expert advising and training has been established with content leaders at our institution, and will undertake training in lab management, leadership in team science, genomic data science, seminars in the biology of metastasis through coursework in the school of medicine, and the NCI’s Bioinformatics Training and Education Program. My goal is to advance as an independent surgeon-scientist, achieving a NIH K08 career development award over the course of this program. Through this work, we hope to be...