Title: Unravelling mechanisms of cell competition in pancreatic cancer initiation. Potential novel targets for early detection
Funder: Cancer Research UK

Abstract: Pancreatic cancer is a deadly incurable disease with poor prognosis, predicted to become the fourth biggest cancer killer over the next decade. Early detection is vital to improving current survival rates and to prevent escalating numbers of deaths in the future. Current diagnostic strategies are unable to identify early non-malignant disease, or distinguish an early cancer diagnosis from other pancreas pathologies. A better understanding of the biology of early disease will support development of new and improved early detection methods. KRas mutations (KRasG12D) are the principal oncogenic drivers of human pancreatic ductal adenocarcinoma (PDAC). The majority (90%) of human PDAC arises sporadically, and originates from precursor lesions, predominantly (~90%) pancreatic intraepithelial neoplasia (PanIN). The clinical and biological relevance of PanINs (particularly low grade) as precursors to malignant PDAC remains elusive. Our research demonstrates that competitive interactions with normal cells drive the segregation and subsequent elimination of Ras-transformed cells from epithelial tissues. Cell competition is a general cell-cell monitoring system that eliminates aberrant or unfit cells to maintain tissue health and homeostasis. Our research suggests that in order to survive and expand in healthy tissues, KRasG12D cells must be able to override competitive signals from normal cells. The mechanisms underlying how normal cells detect mutant cells, and how mutant cells override these signals remain poorly defined. We have established an in vivo mouse model of cell competition in adult pancreas, which recapitulates the initial stages of sporadic human disease. Current data demonstrate that KRasG12D cells become contractile, segregate from surrounding tissue, and are selectively eliminated when present in healthy tissues at low numbers, suggesting cell competition. The goal of this proposal is to unravel the mechanisms underlying how KRasG12D cells outcompete normal neighbours during the very first stages of PDAC tumorigenesis. We will test the hypothesis that additional pro-tumorigenic mutations confer a competitive advantage to KRasG12D cells. Using fluorescent reporters of Cre, we visualise and trace mutant cells in vivo. Quantitative 3D imaging, combined with transcriptomic approaches will enable us to determine the mechanisms of competitive interactions within a complex tissue structure. This research underpins early detection discovery by identifying novel regulators of premalignant disease.

Lay abstract: Pancreatic cancer is a deadly incurable disease with poor prognosis, predicted to become the fourth biggest cancer killer over the next decade. Early detection is vital to improving current survival rates and to prevent escalating numbers of deaths in the future. Current diagnostic strategies are unable to identify early non-malignant disease, or distinguish an early cancer diagnosis from other pancreas pathologies. A better understanding of the biology of early disease will support development of new and improved early detection methods. KRas mutations (KRasG12D) are the principal oncogenic drivers of human pancreatic ductal adenocarcinoma (PDAC). The majority (90%) of human PDAC arises sporadically, and originates from precursor lesions, predominantly (~90%) pancreatic intraepithelial neoplasia (PanIN). The clinical and biological relevance of PanINs (particularly low grade) as precursors to malignant PDAC remains elusive. Our research demonstrates that competitive interactions with normal cells drive the segregation and subsequent elimination of Ras-transformed cells from epithelial tissues. Cell competition is a general cell-cell monitoring system that eliminates aberrant or unfit cells to maintain tissue health and homeostasis. Our research suggests that in order to survive and expand in healthy tissues, KRasG12D cells must be able to override competitive signals from normal cells. The mechanisms underlying how normal cells detect mutant cells, and how mutant cells override these signals remain poorly defined. We have established an in vivo mouse model of cell competition in adult pancreas, which recapitulates the initial stages of sporadic human disease. Current data demonstrate that KRasG12D cells become contractile, segregate from surrounding tissue, and are selectively eliminated when present in healthy tissues at low numbers, suggesting cell competition. The goal of this proposal is to unravel the mechanisms underlying how KRasG12D cells outcompete normal neighbours during the very first stages of PDAC tumorigenesis. We will test the hypothesis that additional pro-tumorigenic mutations confer a competitive advantage to KRasG12D cells. Using fluorescent reporters of Cre, we visualise and trace mutant cells in vivo. Quantitative 3D imaging, combined with transcriptomic approaches will enable us to determine the mechanisms of competitive interactions within a complex tissue structure. This research underpins early detection discovery by identifying novel regulators of premalignant disease.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS