Establishment of a reference single-cell RNA sequencing dataset for human pancreatic adenocarcinoma

Chijimatsu, Ryota; Kobayashi, Shogo; Takeda, Yu; Kitakaze, Masatoshi; Tatekawa, Shotaro; Arao, Yasuko; Nakayama, Mika; Tachibana, Naohiro; Saito, Taku; Ennishi, Daisuke; Tomida, Shuta; Sasaki, Kazuki; Yamada, Daisaku; Tomimaru, Yoshito; Takahashi, Hidenori; Okuzaki, Daisuke; Motooka, Daisuke; Ohshiro, Takahito; Taniguchi, Masateru; Suzuki, Yutaka; Ogawa, Kazuhiko; Mori, Masaki; Doki, Yuichiro; Eguchi, Hidetoshi; Ishii, Hideshi

doi:10.1016/j.isci.2022.104659

Cited by 24 publications

(37 citation statements)

References 78 publications

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“…Among the big 4 driver mutations, KRAS plays a dominant role in the occurrence and development of PDAC in animals and humans ( (accessed on 1 August 2022)) [ 29 , 30 , 31 ]. Alterations in cyclin-dependent kinase inhibitors result in uncontrolled cancer cell growth by constitutive activation of cyclin-dependent kinases accelerating cell cycle progression from G1/S to G2/M through their checkpoints, which will give rise to strong proliferative phenotypes [ 32 ].…”

Section: Diagnosis Through Methods Other Than Dna Sequencingmentioning

confidence: 99%

“…Previous studies have shown that the neoplastic epithelium of PDAC exists within a dense desmoplastic stroma, a recognized critical mediator of disease progression through direct effects on cancer cells and indirect effects on the TME, including antitumor immunity, as shown by the studies on in vitro cell culture, in vivo murine models, and human tissues of PDAC [ 76 ]. Recently, reports on single-cell RNA sequencing in several cohorts of human PDAC tissues have been published [ 31 , 77 , 78 , 79 , 80 , 81 ]. By characterizing 136,000 single cells from more than 70 cases with PDAC, the study classifies myoblastic CAF (myCAFs) with a vital pathway of myofibroblasts and EMT and inflammatory CAF (iCAFs) with an inflammatory pathway [ 31 , 77 ].…”

Section: Diagnosis Through Methods Other Than Dna Sequencingmentioning

confidence: 99%

“…Recently, reports on single-cell RNA sequencing in several cohorts of human PDAC tissues have been published [ 31 , 77 , 78 , 79 , 80 , 81 ]. By characterizing 136,000 single cells from more than 70 cases with PDAC, the study classifies myoblastic CAF (myCAFs) with a vital pathway of myofibroblasts and EMT and inflammatory CAF (iCAFs) with an inflammatory pathway [ 31 , 77 ]. Interestingly, the information of single-cell RNA sequencing emerged as a common strategy.…”

Section: Diagnosis Through Methods Other Than Dna Sequencingmentioning

confidence: 99%

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Pancreatic Cancer Research beyond DNA Mutations

et al. 2022

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Pancreatic ductal adenocarcinoma (PDAC) is caused by genetic mutations in four genes: KRAS proto-oncogene and GTPase (KRAS), tumor protein P53 (TP53), cyclin-dependent kinase inhibitor 2A (CDKN2A), and mothers against decapentaplegic homolog 4 (SMAD4), also called the big 4. The changes in tumors are very complex, making their characterization in the early stages challenging. Therefore, the development of innovative therapeutic approaches is desirable. The key to overcoming PDAC is diagnosing it in the early stages. Therefore, recent studies have investigated the multifaced characteristics of PDAC, which includes cancer cell metabolism, mesenchymal cells including cancer-associated fibroblasts and immune cells, and metagenomics, which extend to characterize various biomolecules including RNAs and volatile organic compounds. Various alterations in the KRAS-dependent as well as KRAS-independent pathways are involved in the refractoriness of PDAC. The optimal combination of these new technologies is expected to help treat intractable pancreatic cancer.

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Section: Diagnosis Through Methods Other Than Dna Sequencingmentioning

confidence: 99%

Section: Diagnosis Through Methods Other Than Dna Sequencingmentioning

confidence: 99%

Section: Diagnosis Through Methods Other Than Dna Sequencingmentioning

confidence: 99%

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Pancreatic Cancer Research beyond DNA Mutations

et al. 2022

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“…The importance of crosstalk between epithelium, CAF and macrophage compartments has been re-emphasised by recent findings of overlap between CAF ligands which affect tumour cells and those expressed by macrophages also. This implies the role of macrophage coupling with fibroblasts, and the possibility of therapeutic targeting of this partnership [ 115 ] ( Figure 4 ).…”

Section: Tumour-stroma Crosstalk Influences the Tme And Clinical Phen...mentioning

confidence: 99%

Exploring the Biology of Cancer-Associated Fibroblasts in Pancreatic Cancer

Bryce

Dreyer

Froeling

et al. 2022

Cancers

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Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy characterised by a stubbornly low 5-year survival which is essentially unchanged in the past 5 decades. Despite recent advances in chemotherapy and surgical outcomes, progress continues to lag behind that of other cancers. The PDAC microenvironment is characterised by a dense, fibrotic stroma of which cancer-associated fibroblasts (CAFs) are key players. CAFs and fibrosis were initially thought to be uniformly tumour-promoting, however this doctrine is now being challenged by a wealth of evidence demonstrating CAF phenotypic and functional heterogeneity. Recent technological advances have allowed for the molecular profiling of the PDAC tumour microenvironment at exceptional detail, and these technologies are being leveraged at pace to improve our understanding of this previously elusive cell population. In this review we discuss CAF heterogeneity and recent developments in CAF biology. We explore the complex relationship between CAFs and other cell types within the PDAC microenvironment. We discuss the potential for therapeutic targeting of CAFs, and we finally provide an overview of future directions for the field and the possibility of improving outcomes for patients with this devastating disease.

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“…Eventually, studies on mutation-prone tumors indicated that the mismatch-repair status predicted the clinical benefit of immune checkpoint blockade with antiprogrammed cell death 1 reagents (10)(11)(12), suggesting that genetic mutations and resultant production of aberrant peptides or proteins may sensitize the response to cancer therapy. Recent studies have emerged that the importance of the regulation of aberrant protein production (RAPP) in many secretary and membrane proteins (13)(14)(15)(16), playing a role in epithelial cancer cell and activated fibroblast or immune cell communication, the process associated with patient survival (6). In this article, we focused on the mechanism of RAPP in gastrointestinal cancer, especially pancreatic cancer, and explored the possibility of an innovative approach against intractable cancers.…”

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confidence: 99%

Targeting the regulation of aberrant protein production pathway in gastrointestinal cancer treatment

et al. 2022

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Recent single-cell level sequence analysis in pancreatic cancer, which is a representative of intractable gastrointestinal cancers, revealed that the tumor tissue comprised of not only epithelial malignant cancer cells but also stromal activated fibroblasts and infiltrated immune cells. This indicates that various changes in gene expression occur in cells, including changes in cell-to-cell communication, to form a microenvironment that is characteristic of cancer (1-6). Epithelial malignant cancer cells harbor "big 4" driver mutations, that is, substitutions or alterations of nucleotides in KRAS proto-oncogene, GTPase (KRAS), tumor protein P53 (TP53), and cyclindependent kinase inhibitor 2A (CDKN2A), and mothers against decapentaplegic homolog 4 (SMAD4) commonly occurs in pancreatic ductal adenocarcinoma (PDAC) (https://portal.gdc.cancer.gov), which can be useful for predicting survival in patients with resected PDAC (7). Conversely, numerous gene expression alterations, due to cancer-specific transcription, RNA processing, and translations, are demonstrated by mesenchymal components, which include activated fibroblasts, vascular endothelial cells, and immune cells (8, 9). Importantly, this cancer-specific alterations induce the production of abnormal peptides and proteins with deleterious degenerations, which led to anti-apoptotic and pro-survival signals in cell-to-cell communication among tumor-component cells, contributing to biologically malignant phenotypes such as epithelial-to-mesenchymal transition phenotypes, invasion, and metastasis (8, 9). Thus, the aberrant protein production is important for the development of cancer-specific Frontiers in Oncology frontiersin.org 01

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Establishment of a reference single-cell RNA sequencing dataset for human pancreatic adenocarcinoma

Cited by 24 publications

References 78 publications

Pancreatic Cancer Research beyond DNA Mutations

Pancreatic Cancer Research beyond DNA Mutations

Exploring the Biology of Cancer-Associated Fibroblasts in Pancreatic Cancer

Targeting the regulation of aberrant protein production pathway in gastrointestinal cancer treatment

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