Visualization of stem cell activity in pancreatic cancer expansion by direct lineage tracing with live imaging

Maruno, Takahisa; Fukuda, Akira; Goto, Norihiro; Tsuda, Motoyuki; Ikuta, Kozo; Hiramatsu, Yukiko; Ogawa, Satoshi; Nakanishi, Yuki; Yamaga, Yuichi; Yoshioka, Taiyo; Takaori, Kyoichi; Üemoto, Shinji; Saur, Dieter; Chiba, Tsutomu; Seno, Hiroshi

doi:10.7554/elife.55117

Cited by 22 publications

(21 citation statements)

References 30 publications

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“…Doublecortin-like kinase 1 (Dclk1) is a microtubuleassociated protein kinase that was originally known as a tuft cell marker in the intestine [22]. However, Dclk1 is also a marker of TSCs in many cancers, including human CRC [23][24][25][26]. We previously used lineage tracing to demonstrate the stem cell properties of Dclk1-positive (Dclk1 + ) cells in intestinal tumors [27].…”

Section: Introductionmentioning

confidence: 99%

Brg1 is required to maintain colorectal cancer stem cells

Yoshikawa

Fukuda

Omatsu

et al. 2021

The Journal of Pathology

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Tumor cells capable of self-renewal and continuous production of progeny cells are called tumor stem cells (TSCs) and are considered to be potential therapeutic targets. However, the mechanisms underlying the survival and function of TSCs are not fully understood. We previously reported that chromatin remodeling regulator Brg1 is essential for intestinal stem cells in mice and Dclk1 is an intestinal TSC marker. In this study, we investigated the role of Brg1 in Dclk1 + intestinal tumor cells for the maintenance of intestinal tumors in mice. Specific ablation of Brg1 in Dclk1 + intestinal tumor cells reduced intestinal tumors in Apc Min mice, and continuous ablation of Brg1 maintained the reduction of intestinal tumors. Lineage tracing in the context of Brg1 ablation in Dclk1 + intestinal tumor cells revealed that Brg1-null Dclk1 + intestinal tumor cells did not give rise to their descendent tumor cells, indicating that Brg1 is essential for the self-renewal of Dclk1 + intestinal tumor cells. Five days after Brg1 ablation, we observed increased apoptosis in Dclk1 + tumor cells. Furthermore, Brg1 was crucial for the stemness of intestinal tumor cells in a spheroid culture system. BRG1 knockdown also impaired cell proliferation and increased apoptosis in human colorectal cancer (CRC) cells. Microarray analysis revealed that apoptosis-related genes were upregulated and stem cell-related genes were downregulated in human CRC cells by BRG1 suppression. Consistently, high BRG1 expression correlated with poor disease-specific survival in human CRC patients. These data indicate that Brg1 plays a crucial role in intestinal TSCs in mice by inhibiting apoptosis and is critical for cell survival and stem cell features in human CRC cells. Thus, BRG1 represents a new therapeutic target for human CRC.

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Section: Introductionmentioning

confidence: 99%

Brg1 is required to maintain colorectal cancer stem cells

Yoshikawa

Fukuda

Omatsu

et al. 2021

The Journal of Pathology

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“…As described earlier, CSC properties can be tested with various assays. Using these assays, many pancreatic CSC markers have been discovered, including, CD133 [14,[114][115][116], CD24 [15,117,118], CD44 [15,117,119,120], ESA [15], Nestin [121], and Dclk1 [90,113,122] or a combination of these markers [14,15] (Figure 3). In addition, it has been shown that migration of CD133 + /CXCR4 + cancer cells is essential in metastasis formation of human pancreatic cancer [14] (Figure 3).…”

Section: Stem Cell Identification and Functionality In Panin Pdac And Metastasismentioning

confidence: 99%

Stem Cells in the Exocrine Pancreas during Homeostasis, Injury, and Cancer

Lodestijn

Neerven

Vermeulen

et al. 2021

Cancers

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Cell generation and renewal are essential processes to develop, maintain, and regenerate tissues. New cells can be generated from immature cell types, such as stem-like cells, or originate from more differentiated pre-existing cells that self-renew or transdifferentiate. The adult pancreas is a dormant organ with limited regeneration capacity, which complicates studying these processes. As a result, there is still discussion about the existence of stem cells in the adult pancreas. Interestingly, in contrast to the classical stem cell concept, stem cell properties seem to be plastic, and, in circumstances of injury, differentiated cells can revert back to a more immature cellular state. Importantly, deregulation of the balance between cellular proliferation and differentiation can lead to disease initiation, in particular to cancer formation. Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with a 5-year survival rate of only ~9%. Unfortunately, metastasis formation often occurs prior to diagnosis, and most tumors are resistant to current treatment strategies. It has been proposed that a specific subpopulation of cells, i.e., cancer stem cells (CSCs), are responsible for tumor expansion, metastasis formation, and therapy resistance. Understanding the underlying mechanisms of pancreatic stem cells during homeostasis and injury might lead to new insights to understand the role of CSCs in PDAC. Therefore, in this review, we present an overview of the current literature regarding the stem cell dynamics in the pancreas during health and disease. Furthermore, we highlight the influence of the tumor microenvironment on the growth behavior of PDAC.

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“…Recently, using genetic lineage tracing with a dual‐recombinase system and live imaging, it was shown that doublecortin‐like kinase 1‐positive [Dclk1(+)] tumor cells can continuously produce progeny cells in pancreatic intraepithelial neoplasia, primary and metastatic pancreatic ductal adenocarcinoma (PDAC), and PDAC‐derived spheroids (Sphs) in vivo and in vitro 25 . Furthermore, genes associated with CSC and EMT were enriched in mouse Dclk1(+) and human DCLK1‐high PDAC cells 25 . In the present study, we found that SNAIL2 is highly expressed among the EMT‐TFs including, SNAIL, TWIST, and ZEB family members, in human pancreatic cancer cell lines and patient‐derived Sphs.…”

Section: Introductionmentioning

confidence: 99%

SNAIL2 contributes to tumorigenicity and chemotherapy resistance in pancreatic cancer by regulating IGFBP2

et al. 2021

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Pancreatic cancer has an extremely poor prognosis because of its resistance to conventional therapies. Cancer stem cell (CSC)‐targeted therapy is considered a promising approach for this disease. Epithelial‐mesenchymal transition‐inducing transcription factors (EMT‐TFs) contribute to CSC properties in some solid tumors; however, this mechanism has not been fully elucidated in pancreatic cancer. Zinc finger protein, SNAIL2 (also known as SLUG), is a member of the SNAIL superfamily of EMT‐TFs and is commonly overexpressed in pancreatic cancer. Patients exhibiting high SNAIL2 expression have a poor prognosis. In this study, we showed that the suppression of SNAIL2 expression using RNA interference decreased tumorigenicity in vitro (sphere formation assay) and in vivo (xenograft assay) in 2 pancreatic cancer cell lines, KLM1 and KMP5. In addition, SNAIL2 suppression resulted in increased sensitivity to gemcitabine and reduced the expression of CD44, a pancreatic CSC marker. Moreover, experiments on tumor spheroids established from surgically resected pancreatic cancer tissues yielded similar results. A microarray analysis revealed that the mechanism was mediated by insulin‐like growth factor (IGF) binding protein 2. These results indicate that IGFBP2 regulated by SNAIL2 may represent an effective therapeutic target for pancreatic cancer.

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Visualization of stem cell activity in pancreatic cancer expansion by direct lineage tracing with live imaging

Cited by 22 publications

References 30 publications

Brg1 is required to maintain colorectal cancer stem cells

Brg1 is required to maintain colorectal cancer stem cells

Stem Cells in the Exocrine Pancreas during Homeostasis, Injury, and Cancer

SNAIL2 contributes to tumorigenicity and chemotherapy resistance in pancreatic cancer by regulating IGFBP2

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