Biology subjects

Baldan, J.

Publications and source records attributed to Baldan, J..

4 recordsLinked to original sources

bioRxiv2025

Spatial map of native duct cell populations in human pancreas and their representation in pancreatic cancers

BackgroundA resemblance of pancreatic tumors to their native tissue architecture remains largely unexplored, while it may reveal novel insights into the healthy and diseased tissue. ObjectiveThis study aims at generating a spatially resolved map of human pancreatic duct cell populations in the native tissue and in tumors, i.e. pancreatic ductal adenocarcinoma (PDAC) and adenosquamous cancer of the pancreas (ASCP). DesignNew datasets were acquired with several spatial transcriptomics platforms and were integrated with public single-cell RNAseq datasets and validated by multiplex immunofluorescence. Cell lines and primary human cell cultures were genetically manipulated. ResultsGroups of Keratin-5+ cells in larger ducts have a gene signature reminiscent of stem cells and (supra)basal cells from other tissues. At single cell resolution, this group comprises {Delta}Np63+ basal cells (BAS) and {Delta}Np63- supra-basally residing luminal-B cells (LUM-B). The latter express previously unreported MUC4 and MUC16. Additionally, we identified three other luminal cell populations in the ducts (LUM-A, -C, -D). In cancer, BAS and LUM-B signatures associate with basal-like (BL) PDAC, and correlate with lower survival. However, PDAC exhibits a random spatial pattern and fragmented native expression programs while ASCP preserve the identity of LUM-B and BAS in a spatially unmixed pattern. {Delta}Np63 drives cell plasticity to BAS, conserved from the native tissue to cancer. ConclusionSpatially distinct duct cell populations are revealed, and the extent of preservation of the native cell identities in pancreatic cancer underpins distinct tumor identities. This warrants a separate consideration in research and therapy. What is already known on this topicWhile tumors in the pancreas can exhibit basal-like and squamous features resembling tumors of other tissues, their resemblance to the native duct cells, and possible subpopulations thereof, had not been studied in detail. What this study addsOne basal and four luminal spatially distinct cell populations exist in human pancreatic ducts. These are best conserved in ASCP while PDAC shows loss of the native cell identity program. How this study might affect research, practice or policyOur study demonstrates fundamental differences between the tumor cells of the BL PDAC versus the rare ASCP, highlighting the necessity for a clear distinction between them in research and in tumor-specific treatments. Meanwhile, the research community should acknowledge the spatial and functional heterogeneity of human duct cells, including in their experimental models.

cancer biology↗

bioRxiv2024

ΔNP63 defines an exocrine-committed multipotent progenitor subset in the murine pancreas

Cellular plasticity underpins heterogeneity in embryogenic progenitor cells and cancer cells. The transcription factor deltaNp63 ({Delta}Np63) has been implicated in regulating cellular plasticity in several epithelial tissues. Despite a recently established role in steering plasticity of pancreatic cancer, {Delta}Np63 remains unstudied in pancreatic development. Using murine single-cell sequencing data and RNA and protein in situ stainings, we assessed the spatio-temporal expression of Trp63 and {Delta}NP63 in the embryonic pancreas. {Delta}NP63 demonstrates a transient and spatially restricted expression in the multipotent pancreatic progenitor (MPP) compartment delineating pro-exocrine progenitor cells. Lineage tracing of TP63+ cells marks a subset of MPPs and descendant exocrine acinar and centro-acinar/terminal duct cells. Lack of {Delta}NP63 in knock-out mice leads to hypotrophic exocrine acini with reduced levels of differentiation markers. In summary, {Delta}Np63 confers heterogeneity within the MPP compartment, supporting exocrine cell development. These new insights in developmental plasticity have potential implications for pancreatic regeneration and cancer.

developmental biology↗

bioRxiv2024

Tumor microenvironment acidosis favors pancreatic cancer stem cell properties and in vivo metastasis

The acidic tumor microenvironment favors cancer aggressiveness via incompletely understood pathways. Here, we asked whether acidic environments select for cancer stem cell (CSC) properties. Bulk RNA-seq of Panc-1 human pancreatic cancer cells adapted to extracellular pH 6.5 revealed upregulation of CSC markers including CD44, EpCam, Nestin and aldehyde dehydrogenases, and CSC pathway enrichment. We therefore assessed CSC characteristics of acid-adapted (AA) and non-adapted (Ctrl) PaTu8988s and MiaPaca-2 pancreatic cancer cells. Compared to Ctrl, AA cells exhibited increased ALDH- and {beta}-catenin activity and pancreatosphere-forming efficiency, classical CSC characteristics. Panc-1, PaTu8988s and MiaPaCa-2 AA cells differed in CSC marker expression, and AA cells did not exhibit typical flow cytometric CSC populations. However, single-nucleus sequencing identified the acid adaptation-induced emergence of a population with clear CSC characteristics. Finally, in an orthotopic mouse model, AA Panc-1 cells drove strongly increased aggressiveness and liver metastasis compared to Ctrl cells. We conclude that acid-adaptation of pancreatic cancer cells leads to enrichment of a CSC phenotype with unusual traits, providing new insight into how acidic tumor microenvironments favor cancer aggressiveness.

cancer biology↗

bioRxiv2020

MECOM permits pancreatic acinar cell dedifferentiation avoiding cell death under stress conditions

Maintenance of the pancreatic acinar cell phenotype suppresses tumor formation. Hence, repetitive acute or chronic pancreatitis, stress conditions in which the acinar cells dedifferentiate, predispose for cancer formation in the pancreas. Dedifferentiated acinar cells acquire a large panel of duct cell-specific markers. However, it remains unclear to what extent dedifferentiated acini differ from native duct cells and which genes are uniquely regulating acinar cell dedifferentiation. Moreover, most studies have been performed in mice since the availability of human cells is scarce. Here, we applied a non-genetic lineage tracing method of human pancreatic exocrine acinar and duct cells that allowed cell-type-specific gene expression profiling by RNA sequencing. Subsequent to this discovery analysis, one transcription factor that was unique for dedifferentiated acinar cells was functionally characterized. RNA sequencing analysis showed that human dedifferentiated acinar cells expressed genes in Pathways of cancer with prominence of MECOM (EVI-1), a transcription factor that was not expressed by duct cells. During mouse embryonic development, pre-acinar cells also transiently expressed MECOM and in the adult mouse pancreas, MECOM was re-expressed when mice were subjected to acute and chronic pancreatitis, conditions in which acinar cells dedifferentiate. In human cells and in mice, MECOM expression correlated with and was directly regulated by SOX9. Mouse acinar cells that, by genetic manipulation, lose the ability to upregulate MECOM showed impaired cell adhesion, more prominent acinar cell death and suppressed acinar cell dedifferentiation by limited ERK signaling. In conclusion, we transcriptionally profiled the two major human pancreatic exocrine cell types, acinar and duct cells, during experimental stress conditions. We provide insights that in dedifferentiated acinar cells, cancer pathways are upregulated in which MECOM is a critical regulator that suppresses acinar cell death by permitting cellular dedifferentiation.

cancer biology↗