Pancreatic circulating tumor cell profiling identifies LIN28B as a metastasis driver and drug target

Franses, Joseph W.; Philipp, Julia; Missios, Pavlos; Bhan, Irun; Liu, Ann; Yashaswini, Chittampalli; Tai, Eric C.; Zhu, Huili; Ligorio, Matteo; Nicholson, Benjamin; Tassoni, Elizabeth M.; Desai, Niyati; Kulkarni, Anupriya S.; Szabolcs, Annamária; Hong, Theodore S.; Liss, Andrew S.; Castillo, Carlos Fernández‐del; Ryan, David P.; Maheswaran, Shyamala; Haber, Daniel A.; Daley, George Q.; Ting, David T.

doi:10.1038/s41467-020-17150-3

Cited by 65 publications

(45 citation statements)

References 59 publications

(70 reference statements)

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“…The EMT marker expressed in CTCs is closely related to poor clinical results. As mentioned in previous studies, puerarin inhibits migration and invasion by antagonizing EMT [33]. We studied the effects of puerarin on PCC proliferation, apoptosis, migration, and invasion, tumor growth, and metastasis in a PDAC xenograft mouse model.…”

Section: Discussionmentioning

confidence: 92%

The Isoflavone Puerarin Exerts Anti-Tumor Activitiy in Pancreatic Ductal Adenocarcinoma by Suppressing Akt/mTOR Activity

Zhu

Lü

Xiao

et al. 2021

Preprint

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Background: Puerarin (7,4’-dihydroxyisoflavone-8-β-glucopyranoside) is a natural flavonoid compound isolated from the traditional Chinese herb Radix puerariae. Recent studies have demonstrated that puerarin has potential anti-tumor effects via induction of apoptosis and inhibition of proliferation. However, the effect and molecular mechanism of puerarin in pancreatic ductal adenocarcinoma (PDAC) remains unknown.Methods: The effects of puerarin on the proliferation, apoptosis, migration and invasion of pancreatic cancer cells (PCCs), and tumor growth and metastasis in PDAC xenograft mouse model were performed. In addition, Akt/mTOR signaling activity was evaluated both in vivo and in vitro.Results: Puerarin treatment significantly repressed PCC proliferation in concentration- and time-dependent manners. Puerarin induced the mitochondrial-dependent apoptosis of PCCs by causing a Bcl-2/Bax imbalance. Moreover, puerarin inhibited PCC migration and invasion by antagonizing epithelial-mesenchymal transition (EMT). In nude mouse model, PDAC growth and metastasis were reduced by puerarin administration. Mechanistically, puerarin exerted its therapeutic effects on PDAC by suppressing Akt/mTOR signaling. Importantly, puerarin bound to the kinase domain of mTOR protein, affecting the activity of the surrounding amino acid residues associated with the binding of the ATP-Mg2+ complex. Further studies showed that the inhibitory effects of puerarin on PCCs were abolished by a mTOR activator MHY1485, indicating a crucial role of mTOR in anti-tumor effects of puerarin in PDAC. As a result, puerarin hindered glucose uptake and metabolism by downregulating the oxygen consumption rate (OCR) and the extracellular acidification rate (ECAR) dependent upon HIF-1α and glucose transporter GLUT1.Conclusion: Puerarin has therapeutic potential for the treatment of PDAC by suppressing Akt/mTOR activity.

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Section: Discussionmentioning

confidence: 92%

The Isoflavone Puerarin Exerts Anti-Tumor Activitiy in Pancreatic Ductal Adenocarcinoma by Suppressing Akt/mTOR Activity

Zhu

Lü

Xiao

et al. 2021

Preprint

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“…CTCs are considered to be responsible for the distant metastasis of tumors [ 21 ]. As a liquid biopsy, CTC enumeration could predict disease progression and treatment response, while molecular analysis may provide deep insights into mechanisms of tumor metastasis and guide the development of therapeutic strategies [ 22 , 23 , 24 ]. In recent years, advancements in microfluidic techniques have provided us lots of new tools for cellular biology studies.…”

Section: Discussionmentioning

confidence: 99%

Design and Clinical Application of an Integrated Microfluidic Device for Circulating Tumor Cells Isolation and Single-Cell Analysis

Liu

Zou

et al. 2021

Micromachines

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Circulating tumor cells (CTCs) have been considered as an alternative to tissue biopsy for providing both germline-specific and tumor-derived genetic variations. Single-cell analysis of CTCs enables in-depth investigation of tumor heterogeneity and individualized clinical assessment. However, common CTC enrichment techniques generally have limitations of low throughput and cell damage. Herein, based on micropore-arrayed filtration membrane and microfluidic chip, we established an integrated CTC isolation platform with high-throughput, high-efficiency, and less cell damage. We observed a capture rate of around 85% and a purity of 60.4% by spiking tumor cells (PC-9) into healthy blood samples. Detection of CTCs from lung cancer patients demonstrated a positive detectable rate of 87.5%. Additionally, single CTCs, ctDNA and liver biopsy tissue of a representative advanced lung cancer patient were collected and sequenced, which revealed comprehensive genetic information of CTCs while reflected the differences in genetic profiles between different biological samples. This work provides a promising tool for CTCs isolation and further analysis at single-cell resolution with potential clinical value.

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“…Both datasets were generated on an AB 5500xl Genetic Analyzer on GPL15907 ( Mus musculus ) and GPL16288 ( Homo sapiens ) platforms, respectively. Another two RNA-seq datasets of enriched pancreatic CTC samples are also accessible through GEO Series accession number GSE40174 [ 60 ] and GES144561 [ 61 ].…”

Section: Methodsmentioning

confidence: 99%

GAS2L1 Is a Potential Biomarker of Circulating Tumor Cells in Pancreatic Cancer

Zhu

Kan

Grün

et al. 2020

Cancers

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Pancreatic cancer is a malignant disease with high mortality and a dismal prognosis. Circulating tumor cell (CTC) detection and characterization have emerged as essential techniques for early detection, prognostication, and liquid biopsy in many solid malignancies. Unfortunately, due to the low EPCAM expression in pancreatic cancer CTCs, no specific marker is available to identify and isolate this rare cell population. This study analyzed single-cell RNA sequencing profiles of pancreatic CTCs from a genetically engineered mouse model (GEMM) and pancreatic cancer patients. Through dimensionality reduction analysis, murine pancreatic CTCs were grouped into three clusters with different biological functions. CLIC4 and GAS2L1 were shown to be overexpressed in pancreatic CTCs in comparison with peripheral blood mononuclear cells (PBMCs). Further analyses of PBMCs and RNA-sequencing datasets of enriched pancreatic CTCs were used to validate the overexpression of GAS2L1 in pancreatic CTCs. A combinatorial approach using both GAS2L1 and EPCAM expression leads to an increased detection rate of CTCs in PDAC in both GEMM and patient samples. GAS2L1 is thus proposed as a novel biomarker of pancreatic cancer CTCs.

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Pancreatic circulating tumor cell profiling identifies LIN28B as a metastasis driver and drug target

Cited by 65 publications

References 59 publications

The Isoflavone Puerarin Exerts Anti-Tumor Activitiy in Pancreatic Ductal Adenocarcinoma by Suppressing Akt/mTOR Activity

The Isoflavone Puerarin Exerts Anti-Tumor Activitiy in Pancreatic Ductal Adenocarcinoma by Suppressing Akt/mTOR Activity

Design and Clinical Application of an Integrated Microfluidic Device for Circulating Tumor Cells Isolation and Single-Cell Analysis

GAS2L1 Is a Potential Biomarker of Circulating Tumor Cells in Pancreatic Cancer

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