Aldh1b1 expression defines progenitor cells in the adult pancreas and is required for Kras-induced pancreatic cancer

Abstract

The presence of progenitor or stem cells in the adult pancreas and their potential involvement in homeostasis and cancer development remain unresolved issues. Here, we show that mouse centroacinar cells can be identified and isolated by virtue of the mitochondrial enzyme Aldh1b1 that they uniquely express. These cells are necessary and sufficient for the formation of self-renewing adult pancreatic organoids in an Aldh1b1-dependent manner. Aldh1b1-expressing centroacinar cells are largely quiescent, self-renew, and, as shown by genetic lineage tracing, contribute to all 3 pancreatic lineages in the adult organ under homeostatic conditions. Single-cell RNA sequencing analysis of these cells identified a progenitor cell population, established its molecular signature, and determined distinct differentiation pathways to early progenitors. A distinct feature of these progenitor cells is the preferential expression of small GTPases, including Kras, suggesting that they might be susceptible to Kras-driven oncogenic transformation. This finding and the overexpression of Aldh1b1 in human and mouse pancreatic cancers, driven by activated Kras, prompted us to examine the involvement of Aldh1b1 in oncogenesis. We demonstrated genetically that ablation of Aldh1b1 completely abrogates tumor development in a mouse model of KrasG12D-induced pancreatic cancer.

Single-cell transcriptome analysis defines heterogeneity of the murine pancreatic ductal tree

“…DBA is expressed in murine centroacinar/terminal ducts as early as 3 weeks of age ( Stanger et al, 2005 ), thus these cells would be expected to be present in our dataset ( Beer et al, 2016 ). Examination of expression of centroacinar/terminal ductal cell markers Hes1 ( Kopinke et al, 2011 ), Aldh1a1 ( Rovira et al, 2010 ), and Aldh1b1 ( Mameishvili et al, 2019 ) in our dataset showed broad expression enriched in either clusters 0 and 2 ( Hes1 and Aldh1b1 ) or clusters 1 and 4 ( Aldh1a1 ), rather than a distinct subpopulation as is seen in the ALK3 + human scRNA-seq pancreas duct dataset. Aldh1a7 is negligibly expressed in murine duct clusters 0–5 ( Figure 3—figure supplement 3G ).…”

Aldehyde Dehydrogenase 1B1 Is Associated with Altered Cell Morphology, Proliferation, Migration and Chemosensitivity in Human Colorectal Adenocarcinoma Cells

“…Specifically, ALDH1B1 has been found to be involved in β-cell development (in mice) [ 50 ], the maintenance of sperm motility (in horses) [ 51 ] and ethanol and retinaldehyde metabolism (in humans) [ 28 ]. Further studies have demonstrated that ALDH1B1 is associated with diabetes [ 52 ], colon cancer [ 30 , 31 , 32 , 33 ], pancreatic cancer [ 34 , 35 ] and osteosarcoma [ 4 ], as well as in regulating different CSC-related signaling pathways, such as PI3K/Akt, Notch and Wnt/β-catenin [ 30 ]. The overexpression of ALDHs is involved in tumor progression through CSCs [ 53 ], giving cancer cells a survival advantage against oxidative damage, lipid peroxidation and toxic aldehydes, all of which are involved in slowing down cell proliferation [ 54 ].…”

“…ALDH1B1 is a mitochondrial NAD + -dependent enzyme that metabolizes acetaldehyde, 4-hydroxynonenal (4-HNE), malondialdehyde (MDA) [ 28 ], nitroglycerin and retinaldehyde [ 29 ]. Still, little is known about its physiological and pathophysiological roles, but several studies have indicated its association with colorectal [ 30 , 31 , 32 , 33 ], pancreatic [ 34 , 35 ], osteosarcoma [ 4 ], liver [ 36 ], gastric [ 37 ] and lung [ 38 ] tumorigenesis. However, its exact role in carcinogenesis and cancer progression remains elusive.…”

Single cell transcriptome analysis defines heterogeneity of the murine pancreatic ductal tree

“…DBA is expressed in murine centroacinar/terminal ducts as early as three weeks of age (34), thus these cells would be expected to be present in our dataset(11). Examination of centroacinar/terminal ductal cell markers Hes1 (35), Aldh1a1 (36), and Aldh1b1 (37) showed broad expression enriched in either clusters 0 and 2 ( Hes1 and Aldh1b1 ) or clusters 1 and 4 ( Aldh1a1 ), rather than a distinct subpopulation as is seen in the ALK3 + human pancreatic duct dataset. Aldh1a7 is negligibly expressed in murine duct clusters 0-5 (Figure S7G).…”