Pancreatic Cancer Stem Cells May Define Tumor Stroma Characteristics and Recurrence Patterns in Pancreatic Ductal Adenocarcinoma

Askan, Gokce; Şahin, Ibrahim Halil; Chou, Joanne F.; Yavas, Aslihan; Capanu, Marinela; Iacobuzio‐Donahue, Christine A.; Baştürk, Olca; O’Reilly, Eileen M.

doi:10.21203/rs.3.rs-49165/v2

Cited by 4 publications

(5 citation statements)

References 32 publications

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“…The only sample that could not be classified as classical or basal-like expressed a CSC signature. CSCs present a more aggressive behavior and their presence is associated with resistance to therapies, local recurrence, and development of metastasis(53–55). Using ST data, we were able to isolate PanIN ducts and demonstrate that cells expressing CSC features are present in PanINs.…”

Section: Discussionmentioning

confidence: 99%

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PanIN and CAF Transitions in Pancreatic Carcinogenesis Revealed with Spatial Data Integration

Bell

Mitchell

Kiemen

et al. 2022

Preprint

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Spatial transcriptomics (ST) is a powerful approach for cancers molecular and cellular characterization. Pancreatic intraepithelial neoplasia (PanIN) is a pancreatic ductal adenocarcinoma (PDAC) premalignancy diagnosed from formalin-fixed and paraffin-embedded (FFPE) specimens limiting single-cell based investigations. We developed a new FFPE ST analysis protocol for PanINs complemented with novel transfer learning approaches. The first transfer learning approach, to assign cell types to ST spots and integrate the transcriptional signatures, shows that PanINs are surrounded by PDAC cancer associated fibroblasts (CAFs) subtypes, including the rare antigen-presenting CAFs. Furthermore, most PanINs are of the classical PDAC subtype while one sample expresses cancer stem cell markers. A second transfer learning approach, to integrate ST PanIN data with PDAC scRNA-seq data, identifies a shift between inflammatory and proliferative signaling as PanINs progress to PDAC. Our data support a model of inflammatory signaling and PanIN-CAF interactions promoting premalignancy progression and PDAC immunosuppressive characteristics.

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Section: Discussionmentioning

confidence: 99%

“…CSCs drive aggressive disease and their presence is associated with resistance to therapies, local recurrence, and development of metastasis [37][38][39] . The presence of CSCs and CAFs in PanINs suggest that the features associated with resistance to therapies in PDAC arise early during tumorigenesis.…”

Section: Discussionmentioning

confidence: 99%

PanIN and CAF Transitions in Pancreatic Carcinogenesis Revealed with Spatial Data Integration

Bell

Mitchell

Kiemen

et al. 2022

Preprint

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“…Over the last decades, CSCs have garnered great interest owing to their imperative role in virtually all facets of tumor biology, thus making them an attractive target for therapeutic interventions. In PC, mounting evidence has envisaged the potential of targeting PCSCs that can help address cancer regression and prevent relapse of pancreatic malignancies after treatment with therapeutic modalities [11,300]. Indeed, a number of manipulative strategies have been formulated to target PCSCs to manage tumor progression.…”

Section: Clinical Perspective: Targeting Pancreatic Cancer Stem Cells By Phytochemicalsmentioning

confidence: 99%

The plasticity of pancreatic cancer stem cells: implications in therapeutic resistance

Patil

Khan

Akhtar

et al. 2021

Cancer Metastasis Rev

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The ever-growing perception of cancer stem cells (CSCs) as a plastic state rather than a hardwired defined entity has evolved our understanding of the functional and biological plasticity of these elusive components in malignancies. Pancreatic cancer (PC), based on its biological features and clinical evolution, is a prototypical example of a CSC-driven disease. Since the discovery of pancreatic CSCs (PCSCs) in 2007, evidence has unraveled their control over many facets of the natural history of PC, including primary tumor growth, metastatic progression, disease recurrence, and acquired drug resistance. Consequently, the current near-ubiquitous treatment regimens for PC using aggressive cytotoxic agents, aimed at ‘‘tumor debulking’’ rather than eradication of CSCs, have proven ineffective in providing clinically convincing improvements in patients with this dreadful disease. Herein, we review the key hallmarks as well as the intrinsic and extrinsic resistance mechanisms of CSCs that mediate treatment failure in PC and enlist the potential CSC-targeting ‘natural agents’ that are gaining popularity in recent years. A better understanding of the molecular and functional landscape of PCSC-intrinsic evasion of chemotherapeutic drugs offers a facile opportunity for treating PC, an intractable cancer with a grim prognosis and in dire need of effective therapeutic advances.

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“…Many surface markers for CSCs have been proposed in past studies, while CD133 (prominin-1) and CD44 are the most recognized and well-known CSC markers for PC (5)(6)(7). However, it is noteworthy that all currently used CSC markers are only capable of enriching CSCs, largely due to the lack of marker specificity (8)(9)(10).…”

Section: Introductionmentioning

confidence: 99%

GFAT1 is highly expressed in cancer stem cells of pancreatic cancer

Wang¹,

Kuang²,

Wu³

et al. 2022

Ann Transl Med

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Background: Cancer stem cells (CSCs) play pivotal roles in the growth, invasion, metastasis, and chemoresistance of pancreatic cancer (PC). The current characterization of CSCs in PC is not complete.Glutamine-fructose-6-phosphate transaminase 1 (GFAT1) is a key enzyme that regulates the hexosamine pathway (HP), in which it not only controls glucose influx but also catalyzes the reaction to form glucosamine 6-phosphate. Recently, it was reported that GFAT1 is highly expressed in PC. However, the relevance of this high expression of GFAT1, especially its association with cancer stemness, has not been well defined and is thus addressed in the current study.Methods: GFAT1 levels were determined in PC from a public database and assessed by bioinformatics tools. GFAT1 expression in CD133 + and CD44 + CSCs in PC was analyzed by reverse transcriptionquantitative polymerase chain reaction (RT-qPCR) and immunostaining on cytospun cells after flow cytometry-based cell sorting. GFAT1 + cells were separated from GFAT1 − cells by transfection of PC cell lines with a designed plasmid that expressed red fluorescent protein (RFP) under a GFAT1 promoter. Tumor sphere formation, tumor growth, tumor cell invasion, cell migration, and the resistance to gemcitabineinduced apoptosis were determined in GFAT1 + vs. GFAT1 − PC cells.Results: GFAT1 levels were significantly upregulated in PC compared to the adjacent non-PC tissue.There were significantly more GFAT1 + cells in the CD133 + population than in the CD133 − population, and similarly, there were significantly more GFAT1 + cells in the CD44 + population than in the CD44 − population.Compared to GFAT1 − PC cells, GFAT1 + PC cells generated significantly more tumor spheres in culture, appeared to be more invasive and migratory, and were significantly more resistant to gemcitabine-induced cell apoptosis.Conclusions: GFAT1 is highly expressed in CSCs among PC cells and may be crucial for PC growth, metastasis, and chemoresistance.

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Pancreatic Cancer Stem Cells May Define Tumor Stroma Characteristics and Recurrence Patterns in Pancreatic Ductal Adenocarcinoma

Cited by 4 publications

References 32 publications

PanIN and CAF Transitions in Pancreatic Carcinogenesis Revealed with Spatial Data Integration

PanIN and CAF Transitions in Pancreatic Carcinogenesis Revealed with Spatial Data Integration

The plasticity of pancreatic cancer stem cells: implications in therapeutic resistance

GFAT1 is highly expressed in cancer stem cells of pancreatic cancer

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