Publications by authors named "Pengcheng Bu"

34 Publications

Non-coding RNA in cancer.

Essays Biochem 2021 Apr 16. Epub 2021 Apr 16.

Key Laboratory of RNA Biology, Key Laboratory of Protein and Peptide Pharmaceutical, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.

Majority of the human genome is transcribed to RNAs that do not encode proteins. These non-coding RNAs (ncRNAs) play crucial roles in regulating the initiation and progression of various cancers. Given the importance of the ncRNAs, the roles of ncRNAs in cancers have been reviewed elsewhere. Thus, in this review, we mainly focus on the recent studies of the function, regulatory mechanism and therapeutic potential of the ncRNAs including microRNA (miRNA), long ncRNA (lncRNA), circular RNA (circRNA) and PIWI interacting RNA (piRNA), in different type of cancers.
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http://dx.doi.org/10.1042/EBC20200032DOI Listing
April 2021

Creatine promotes cancer metastasis through activation of Smad2/3.

Cell Metab 2021 Jun 2;33(6):1111-1123.e4. Epub 2021 Apr 2.

Key Laboratory of RNA Biology, Key Laboratory of Protein and Peptide Pharmaceutical, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China; Center for Excellence in Biomacromolecules, Chinese Academy of Sciences, Beijing 100101, China. Electronic address:

As one of the most popular nutrient supplements, creatine has been highly used to increase muscle mass and improve exercise performance. Here, we report an adverse effect of creatine using orthotopic mouse models, showing that creatine promotes colorectal and breast cancer metastasis and shortens mouse survival. We show that glycine amidinotransferase (GATM), the rate-limiting enzyme for creatine synthesis, is upregulated in liver metastases. Dietary uptake, or GATM-mediated de novo synthesis of creatine, enhances cancer metastasis and shortens mouse survival by upregulation of Snail and Slug expression via monopolar spindle 1 (MPS1)-activated Smad2 and Smad3 phosphorylation. GATM knockdown or MPS1 inhibition suppresses cancer metastasis and benefits mouse survival by downregulating Snail and Slug. Our findings call for using caution when considering dietary creatine to improve muscle mass or treat diseases and suggest that targeting GATM or MPS1 prevents cancer metastasis, especially metastasis of transforming growth factor beta receptor mutant colorectal cancers.
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http://dx.doi.org/10.1016/j.cmet.2021.03.009DOI Listing
June 2021

CD146 is a Novel ANGPTL2 Receptor that Promotes Obesity by Manipulating Lipid Metabolism and Energy Expenditure.

Adv Sci (Weinh) 2021 Mar 27;8(6):2004032. Epub 2021 Jan 27.

Key Laboratory of RNA Biology Key Laboratory of Protein and Peptide Pharmaceuticals Institute of Biophysics Chinese Academy of Sciences Beijing 100101 China.

Obesity and its related complications pose an increasing threat to human health; however, targetable obesity-related membrane receptors are not yet elucidated. Here, the membrane receptor CD146 is demonstrated to play an essential role in obesity. In particular, CD146 acts as a new adipose receptor for angiopoietin-like protein 2 (ANGPTL2), which is thought to act on endothelial cells to activate adipose inflammation. ANGPTL2 binds to CD146 to activate cAMP response element-binding protein (CREB), which then upregulates CD146 during adipogenesis and adipose inflammation. CD146 is present in preadipocytes and mature adipocytes, where it is mediated by its ligands ANGPTL2 and galectin-1. In preadipocytes, CD146 ablation suppresses adipogenesis, whereas the loss of CD146 in mature adipocytes suppresses lipid accumulation and enhances energy expenditure. Moreover, anti-CD146 antibodies inhibit obesity by disrupting the interactions between CD146 and its ligands. Together, these findings demonstrate that ANGPTL2 directly affects adipocytes via CD146 to promote obesity, suggesting that CD146 can be a potential target for treating obesity.
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http://dx.doi.org/10.1002/advs.202004032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7967059PMC
March 2021

N-methyladenosine modification of MALAT1 promotes metastasis via reshaping nuclear speckles.

Dev Cell 2021 Mar 19;56(5):702-715.e8. Epub 2021 Feb 19.

National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China; Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), Guangzhou 510005, China. Electronic address:

N6-methyladenosine (mA), one of the most prevalent RNA post-transcriptional modifications, is involved in numerous biological processes. In previous studies, the functions of mA were typically identified by perturbing the activity of the methyltransferase complex. Here, we dissect the contribution of mA to an individual-long noncoding RNA-metastasis-associated lung adenocarcinoma transcript 1 (MALAT1). The mutant MALAT1 lacking mA-motifs significantly suppressed the metastatic potential of cancer cells both in vitro and in vivo in mouse. Super-resolution imaging showed that the concatenated mA residues on MALAT1 acted as a scaffold for recruiting YTH-domain-containing protein 1 (YTHDC1) to nuclear speckles. We further reveal that the recognition of MALAT1-mA by YTHDC1 played a critical role in maintaining the composition and genomic binding sites of nuclear speckles, which regulate the expression of several key oncogenes. Furthermore, artificially tethering YTHDC1 onto mA-deficient MALAT1 largely rescues the metastatic potential of cancer cells.
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http://dx.doi.org/10.1016/j.devcel.2021.01.015DOI Listing
March 2021

Author Correction: A recellularized human colon model identifies cancer driver genes.

Nat Biotechnol 2019 Jul;37(7):820

Department of Biomedical Engineering, Cornell University, Ithaca, New York, USA.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41587-019-0163-6DOI Listing
July 2019

is a microRNA safeguard for -induced inflammatory colon oncogenesis.

Elife 2018 12 13;7. Epub 2018 Dec 13.

Center for Genomics and Computational Biology, Duke University, Durham, United States.

Inflammation often induces regeneration to repair the tissue damage. However, chronic inflammation can transform temporary hyperplasia into a fertile ground for tumorigenesis. Here, we demonstrate that the microRNA acts as a central safeguard to protect the inflammatory stem cell niche and reparative regeneration. Although playing little role in regular homeostasis, deficiency leads to colon tumorigenesis after infection. targets both immune and epithelial cells to restrain inflammation-induced stem cell proliferation. targets Interleukin six receptor (IL-6R) and Interleukin 23 receptor (IL-23R) to suppress T helper 17 (Th17) cell differentiation and expansion, targets chemokine CCL22 to hinder Th17 cell recruitment to the colon epithelium, and targets an orphan receptor Interleukin 17 receptor D (IL-17RD) to inhibit IL-17-induced stem cell proliferation. Our study highlights the importance of microRNAs in protecting the stem cell niche during inflammation despite their lack of function in regular tissue homeostasis.
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http://dx.doi.org/10.7554/eLife.39479DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6314783PMC
December 2018

Aldolase B-Mediated Fructose Metabolism Drives Metabolic Reprogramming of Colon Cancer Liver Metastasis.

Cell Metab 2018 Jun 26;27(6):1249-1262.e4. Epub 2018 Apr 26.

Department of Biomedical Engineering, Duke University, Durham, NC 27708, USA. Electronic address:

Cancer metastasis accounts for the majority of cancer-related deaths and remains a clinical challenge. Metastatic cancer cells generally resemble cells of the primary cancer, but they may be influenced by the milieu of the organs they colonize. Here, we show that colorectal cancer cells undergo metabolic reprogramming after they metastasize and colonize the liver, a key metabolic organ. In particular, via GATA6, metastatic cells in the liver upregulate the enzyme aldolase B (ALDOB), which enhances fructose metabolism and provides fuel for major pathways of central carbon metabolism during tumor cell proliferation. Targeting ALDOB or reducing dietary fructose significantly reduces liver metastatic growth but has little effect on the primary tumor. Our findings suggest that metastatic cells can take advantage of reprogrammed metabolism in their new microenvironment, especially in a metabolically active organ such as the liver. Manipulation of involved pathways may affect the course of metastatic growth.
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http://dx.doi.org/10.1016/j.cmet.2018.04.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5990465PMC
June 2018

Matrix metalloproteinase inhibitors enhance the efficacy of frontline drugs against Mycobacterium tuberculosis.

PLoS Pathog 2018 04 26;14(4):e1006974. Epub 2018 Apr 26.

Department of Biological and Environmental Engineering, Cornell University, Ithaca, NY, United States of America.

Mycobacterium tuberculosis (Mtb) remains a grave threat to world health with emerging drug resistant strains. One prominent feature of Mtb infection is the extensive reprogramming of host tissue at the site of infection. Here we report that inhibition of matrix metalloproteinase (MMP) activity by a panel of small molecule inhibitors enhances the in vivo potency of the frontline TB drugs isoniazid (INH) and rifampicin (RIF). Inhibition of MMP activity leads to an increase in pericyte-covered blood vessel numbers and appears to stabilize the integrity of the infected lung tissue. In treated mice, we observe an increased delivery and/or retention of frontline TB drugs in the infected lungs, resulting in enhanced drug efficacy. These findings indicate that targeting Mtb-induced host tissue remodeling can increase therapeutic efficacy and could enhance the effectiveness of current drug regimens.
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http://dx.doi.org/10.1371/journal.ppat.1006974DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5919409PMC
April 2018

Non-coding RNAs in cancer stem cells.

Cancer Lett 2018 05 11;421:121-126. Epub 2018 Jan 11.

Key Laboratory of RNA Biology, Key Laboratory of Protein and Peptide Pharmaceutical, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China; University of Chinese Academy of Sciences, Beijing, 100049, China. Electronic address:

Cancer stem cells (CSCs) have been shown to play a key role in tumor initiation, progression, metastasis, and therapy resistance. Despite their potential clinical importance, the mechanism of CSC regulation is not well understood. Recent evidence suggests that different types of non-coding RNAs (ncRNA), such as microRNA (miRNA) and long non-coding RNA (LncRNA), play a role in regulating CSC growth and replication by modulating transcription factors and downstream signaling pathways activated in CSCs. Here, we review the recent major findings about how they affect stem cell quality acquisition and maintenance in CSCs, as well as metastasis and therapy resistance. Drawing connections between such discoveries could be conducive to the development of novel ncRNA-based therapeutics that can selectively target CSCs and reduce rates of cancer recurrence.
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http://dx.doi.org/10.1016/j.canlet.2018.01.027DOI Listing
May 2018

A Notch positive feedback in the intestinal stem cell niche is essential for stem cell self-renewal.

Mol Syst Biol 2017 04 28;13(4):927. Epub 2017 Apr 28.

School of Electrical and Computer Engineering, Cornell University, Ithaca, NY, USA

The intestinal epithelium is the fastest regenerative tissue in the body, fueled by fast-cycling stem cells. The number and identity of these dividing and migrating stem cells are maintained by a mosaic pattern at the base of the crypt. How the underlying regulatory scheme manages this dynamic stem cell niche is not entirely clear. We stimulated intestinal organoids with Notch ligands and inhibitors and discovered that intestinal stem cells employ a positive feedback mechanism via direct Notch binding to the second intron of the Notch1 gene. Inactivation of the positive feedback by CRISPR/Cas9 mutation of the binding sequence alters the mosaic stem cell niche pattern and hinders regeneration in organoids. Dynamical system analysis and agent-based multiscale stochastic modeling suggest that the positive feedback enhances the robustness of Notch-mediated niche patterning. This study highlights the importance of feedback mechanisms in spatiotemporal control of the stem cell niche.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5408779PMC
http://dx.doi.org/10.15252/msb.20167324DOI Listing
April 2017

Asymmetric division: An antitumor player?

Mol Cell Oncol 2016 Jul 19;3(4):e1164279. Epub 2016 May 19.

Department of Biological and Environmental Engineering, Cornell University, Ithaca, NY, USA; Department of Biomedical Engineering, Cornell University, Ithaca, NY, USA; Departments of Biomedical Engineering, Duke University, Durham, NC, USA.

miR-34a-mediated asymmetric cell division reins in excessive stem cell expansion during tissue regeneration in the intestine and colon. Loss of miR-34a switches asymmetric division to symmetric division and enhances stem cell proliferation. Asymmetric division also occurs in the early stages of colon cancer stem cells. Mechanistically, miR-34a, Numb, and Notch form a feed-forward loop that specifies cell fate when stem cells divide.
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http://dx.doi.org/10.1080/23723556.2016.1164279DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4972103PMC
July 2016

A recellularized human colon model identifies cancer driver genes.

Nat Biotechnol 2016 08 11;34(8):845-51. Epub 2016 Jul 11.

Department of Biomedical Engineering, Cornell University, Ithaca, New York, USA.

Refined cancer models are needed to bridge the gaps between cell line, animal and clinical research. Here we describe the engineering of an organotypic colon cancer model by recellularization of a native human matrix that contains cell-populated mucosa and an intact muscularis mucosa layer. This ex vivo system recapitulates the pathophysiological progression from APC-mutant neoplasia to submucosal invasive tumor. We used it to perform a Sleeping Beauty transposon mutagenesis screen to identify genes that cooperate with mutant APC in driving invasive neoplasia. We identified 38 candidate invasion-driver genes, 17 of which, including TCF7L2, TWIST2, MSH2, DCC, EPHB1 and EPHB2 have been previously implicated in colorectal cancer progression. Six invasion-driver genes that have not, to our knowledge, been previously described were validated in vitro using cell proliferation, migration and invasion assays and ex vivo using recellularized human colon. These results demonstrate the utility of our organoid model for studying cancer biology.
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http://dx.doi.org/10.1038/nbt.3586DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4980997PMC
August 2016

NOTCH Signaling Regulates Asymmetric Cell Fate of Fast- and Slow-Cycling Colon Cancer-Initiating Cells.

Cancer Res 2016 06 11;76(11):3411-21. Epub 2016 Apr 11.

Department of Biomedical Engineering, Cornell University, Ithaca, New York. School of Electrical and Computer Engineering, Cornell University, Ithaca, New York. Department of Biomedical Engineering, Duke University, Durham, North Carolina.

Colorectal cancer cells with stem-like properties, referred to as colon cancer-initiating cells (CCIC), have high tumorigenic potential. While CCIC can differentiate to promote cellular heterogeneity, it remains unclear whether CCIC within a tumor contain distinct subpopulations. Here, we describe the co-existence of fast- and slow-cycling CCIC, which can undergo asymmetric division to generate each other, highlighting CCIC plasticity and interconvertibility. Fast-cycling CCIC express markers, such as LGR5 and CD133, rely on MYC for their proliferation, whereas slow-cycling CCIC express markers, such as BMI1 and hTERT, are independent of MYC. NOTCH signaling promotes asymmetric cell fate, regulating the balance between these two populations. Overall, our results illuminate the basis for CCIC heterogeneity and plasticity by defining a direct interconversion mechanism between slow- and fast-cycling CCIC. Cancer Res; 76(11); 3411-21. ©2016 AACR.
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http://dx.doi.org/10.1158/0008-5472.CAN-15-3198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4891252PMC
June 2016

Notch signalling regulates asymmetric division and inter-conversion between lgr5 and bmi1 expressing intestinal stem cells.

Sci Rep 2016 05 16;6:26069. Epub 2016 May 16.

Department of Biomedical Engineering, Cornell University, Ithaca, New York, 14853, USA.

Rapidly cycling LGR5+ intestinal stem cells (ISCs) located at the base of crypts are the primary driver of regeneration. Additionally, BMI1 expression is correlated with a slow cycling pool of ISCs located at +4 position. While previous reports have shown interconversion between these two populations following tissue injury, we provide evidence that NOTCH signaling regulates the balance between these two populations and promotes asymmetric division as a mechanism for interconversion in the mouse intestine. In both in vitro and in vivo models, NOTCH suppression reduces the ratio of BMI1+/LGR5+ ISCs while NOTCH stimulation increases this ratio. Furthermore, NOTCH signaling can activate asymmetric division after intestinal inflammation. Overall, these data provide insights into ISC plasticity, demonstrating a direct interconversion mechanism between slow- and fast-cycling ISCs.
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http://dx.doi.org/10.1038/srep26069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4867651PMC
May 2016

A long non-coding RNA targets microRNA miR-34a to regulate colon cancer stem cell asymmetric division.

Elife 2016 04 14;5. Epub 2016 Apr 14.

Department of Biological and Environmental Engineering, Cornell University, Ithaca, United States.

The roles of long non-coding RNAs (lncRNAs) in regulating cancer and stem cells are being increasingly appreciated. Its diverse mechanisms provide the regulatory network with a bigger repertoire to increase complexity. Here we report a novel LncRNA, Lnc34a, that is enriched in colon cancer stem cells (CCSCs) and initiates asymmetric division by directly targeting the microRNA miR-34a to cause its spatial imbalance. Lnc34a recruits Dnmt3a via PHB2 and HDAC1 to methylate and deacetylate the miR-34a promoter simultaneously, hence epigenetically silencing miR-34a expression independent of its upstream regulator, p53. Lnc34a levels affect CCSC self-renewal and colorectal cancer (CRC) growth in xenograft models. Lnc34a is upregulated in late-stage CRCs, contributing to epigenetic miR-34a silencing and CRC proliferation. The fact that lncRNA targets microRNA highlights the regulatory complexity of non-coding RNAs (ncRNAs), which occupy the bulk of the genome.
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http://dx.doi.org/10.7554/eLife.14620DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4859802PMC
April 2016

A miR-34a-Numb Feedforward Loop Triggered by Inflammation Regulates Asymmetric Stem Cell Division in Intestine and Colon Cancer.

Cell Stem Cell 2016 Feb;18(2):189-202

School of Electrical and Computer Engineering, Cornell University, Ithaca, NY 14853, USA; Department of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA; Department of Biological and Environmental Engineering, Cornell University, Ithaca, NY 14853, USA; Department of Biomedical Engineering, Duke University, Durham, NC 27708, USA. Electronic address:

Emerging evidence suggests that microRNAs can initiate asymmetric division, but whether microRNA and protein cell fate determinants coordinate with each other remains unclear. Here, we show that miR-34a directly suppresses Numb in early-stage colon cancer stem cells (CCSCs), forming an incoherent feedforward loop (IFFL) targeting Notch to separate stem and non-stem cell fates robustly. Perturbation of the IFFL leads to a new intermediate cell population with plastic and ambiguous identity. Lgr5+ mouse intestinal/colon stem cells (ISCs) predominantly undergo symmetric division but turn on asymmetric division to curb the number of ISCs when proinflammatory response causes excessive proliferation. Deletion of miR-34a inhibits asymmetric division and exacerbates Lgr5+ ISC proliferation under such stress. Collectively, our data indicate that microRNA and protein cell fate determinants coordinate to enhance robustness of cell fate decision, and they provide a safeguard mechanism against stem cell proliferation induced by inflammation or oncogenic mutation.
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http://dx.doi.org/10.1016/j.stem.2016.01.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4751059PMC
February 2016

IRE1α is an endogenous substrate of endoplasmic-reticulum-associated degradation.

Nat Cell Biol 2015 Dec 9;17(12):1546-55. Epub 2015 Nov 9.

Graduate Program in Biochemistry, Molecular and Cell Biology, Cornell University, Ithaca, New York 14853, USA.

Endoplasmic reticulum (ER)-associated degradation (ERAD) represents a principle quality control mechanism to clear misfolded proteins in the ER; however, its physiological significance and the nature of endogenous ERAD substrates remain largely unexplored. Here we discover that IRE1α, the sensor of the unfolded protein response (UPR), is a bona fide substrate of the Sel1L-Hrd1 ERAD complex. ERAD-mediated IRE1α degradation occurs under basal conditions in a BiP-dependent manner, requires both the intramembrane hydrophilic residues of IRE1α and the lectin protein OS9, and is attenuated by ER stress. ERAD deficiency causes IRE1α protein stabilization, accumulation and mild activation both in vitro and in vivo. Although enterocyte-specific Sel1L-knockout mice (Sel1L(ΔIEC)) are viable and seem normal, they are highly susceptible to experimental colitis and inflammation-associated dysbiosis, in an IRE1α-dependent but CHOP-independent manner. Hence, Sel1L-Hrd1 ERAD serves a distinct, essential function in restraint of IRE1α signalling in vivo by managing its protein turnover.
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http://dx.doi.org/10.1038/ncb3266DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4670240PMC
December 2015

Targeted drug delivery to circulating tumor cells via platelet membrane-functionalized particles.

Biomaterials 2016 Jan 21;76:52-65. Epub 2015 Oct 21.

Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY, 14853, USA. Electronic address:

Circulating tumor cells (CTCs) are responsible for metastases in distant organs via hematogenous dissemination. Fundamental studies in the past decade have suggested that neutralization of CTCs in circulation could represent an effective strategy to prevent metastasis. Current paradigms of targeted drug delivery into a solid tumor largely fall into two main categories: unique cancer markers (e.g. overexpression of surface receptors) and tumor-specific microenvironment (e.g. low pH, hypoxia, etc.). While relying on a surface receptor to target CTCs can be greatly challenged by cancer heterogeneity, targeting of tumor microenvironments has the advantage of recognizing a broader spectrum of cancer cells regardless of genetic differences or tumor types. The blood circulation, however, where CTCs transit through, lacks the same tumor microenvironment as that found in a solid tumor. In this study, a unique "microenvironment" was confirmed upon introduction of cancer cells of different types into circulation where activated platelets and fibrin were physically associated with blood-borne cancer cells. Inspired by this observation, synthetic silica particles were functionalized with activated platelet membrane along with surface conjugation of tumor-specific apoptosis-inducing ligand cytokine, TRAIL. Biomimetic synthetic particles incorporated into CTC-associated micro-thrombi in lung vasculature and dramatically decreased lung metastases in a mouse breast cancer metastasis model. Our results demonstrate a "Trojan Horse" strategy of neutralizing CTCs to attenuate metastasis.
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http://dx.doi.org/10.1016/j.biomaterials.2015.10.046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4662903PMC
January 2016

Comprehensive models of human primary and metastatic colorectal tumors in immunodeficient and immunocompetent mice by chemokine targeting.

Nat Biotechnol 2015 Jun 25;33(6):656-60. Epub 2015 May 25.

Department of Medicine, Weill Cornell Medical College, New York, New York, USA.

Current orthotopic xenograft models of human colorectal cancer (CRC) require surgery and do not robustly form metastases in the liver, the most common site clinically. CCR9 traffics lymphocytes to intestine and colorectum. We engineered use of the chemokine receptor CCR9 in CRC cell lines and patient-derived cells to create primary gastrointestinal (GI) tumors in immunodeficient mice by tail-vein injection rather than surgery. The tumors metastasize inducibly and robustly to the liver. Metastases have higher DKK4 and NOTCH signaling levels and are more chemoresistant than paired subcutaneous xenografts. Using this approach, we generated 17 chemokine-targeted mouse models (CTMMs) that recapitulate the majority of common human somatic CRC mutations. We also show that primary tumors can be modeled in immunocompetent mice by microinjecting CCR9-expressing cancer cell lines into early-stage mouse blastocysts, which induces central immune tolerance. We expect that CTMMs will facilitate investigation of the biology of CRC metastasis and drug screening.
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http://dx.doi.org/10.1038/nbt.3239DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4532544PMC
June 2015

miR-1269 promotes metastasis and forms a positive feedback loop with TGF-β.

Nat Commun 2015 Apr 15;6:6879. Epub 2015 Apr 15.

1] School of Electrical and Computer Engineering, Cornell University, Ithaca, New York 14853, USA [2] Department of Biomedical Engineering, Cornell University, Ithaca, New York 14853, USA [3] Department of Biological and Environmental Engineering, Cornell University, Ithaca, New York 14853, USA.

As patient survival drops precipitously from early-stage cancers to late-stage and metastatic cancers, microRNAs that promote relapse and metastasis can serve as prognostic and predictive markers as well as therapeutic targets for chemoprevention. Here we show that miR-1269a promotes colorectal cancer (CRC) metastasis and forms a positive feedback loop with TGF-β signalling. miR-1269a is upregulated in late-stage CRCs, and long-term monitoring of 100 stage II CRC patients revealed that miR-1269a expression in their surgically removed primary tumours is strongly associated with risk of CRC relapse and metastasis. Consistent with clinical observations, miR-1269a significantly increases the ability of CRC cells to invade and metastasize in vivo. TGF-β activates miR-1269 via Sox4, while miR-1269a enhances TGF-β signalling by targeting Smad7 and HOXD10, hence forming a positive feedback loop. Our findings suggest that miR-1269a is a potential marker to inform adjuvant chemotherapy decisions for CRC patients and a potential therapeutic target to deter metastasis.
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http://dx.doi.org/10.1038/ncomms7879DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4399006PMC
April 2015

A metabolic signature of colon cancer initiating cells.

Annu Int Conf IEEE Eng Med Biol Soc 2014 ;2014:4759-62

Colon cancer initiating cells (CCICs) are more tumorigenic and metastatic than the majority of colorectal cancer (CRC) cells. CCICs have also been associated with stem cell-like properties. However, there is a lack of system-level understanding of what mechanisms distinguish CCICs from common CRC cells. We compared the transcriptomes of CD133+ CCICs and CD133- CRC cells from multiple sources, which identified a distinct metabolic signature for CD133(high) CCICs. High-resolution unbiased metabolomics was then performed to validate this CCIC metabolic signature. Specifically, levels of enzymes and metabolites involved in glycolysis, the citric acid (TCA) cycle, and cysteine and methionine metabolism are altered in CCICs. Analyses of the alterations further suggest an epigenetic link. This metabolic signature provides mechanistic insights into CCIC phenotypes and may serve as potential biomarkers and therapeutic targets for future CRC treatment.
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http://dx.doi.org/10.1109/EMBC.2014.6944688DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4302416PMC
September 2015

Targeting endothelial CD146 attenuates colitis and prevents colitis-associated carcinogenesis.

Am J Pathol 2014 May;184(5):1604-16

Key Laboratory of Protein and Peptide Pharmaceuticals, Center for Infection and Immunity, and the Chinese Academy of Sciences-University of Tokyo Joint Laboratory of Structural Virology and Immunology, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China. Electronic address:

Recently, enhanced CD146 expression was reported on endothelial cells in intestinal biopsies from patients with inflammatory bowel disease. However, the underlying mechanism remains unknown. Here, we found that overexpressed endothelial CD146 promoted the inflammatory responses in inflammatory bowel disease, which further potentiated the occurrence of colitis-associated colorectal carcinogenesis. Eliminating endothelial CD146 by conditional knockout significantly ameliorated the severity of inflammation in two different murine models of colitis, and decreased tumor incidence and tumor progression in a murine model of colitis-associated colorectal carcinogenesis. Mechanistic study showed that cytokine tumor necrosis factor-α (TNF-α) up-regulated the expression of endothelial CD146 through NF-κB transactivation. In turn, the enhanced endothelial CD146 expression promoted both angiogenesis and proinflammatory leukocyte extravasations, contributing to inflammation. Using an anti-CD146 antibody, AA98, alone or together with an anti-TNF-α antibody significantly attenuated colitis and prevented colitis-associated colorectal carcinogenesis in mice. Our study provides the first evidence that CD146 plays a dual role on endothelium, facilitating leukocyte extravasations and angiogenesis, thus promoting inflammation. This finding not only reveals the function and regulating mechanism of CD146 in inflammatory bowel disease, but also provides a promising therapeutic strategy for treating inflammatory bowel disease and preventing colitis-associated colorectal carcinogenesis.
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http://dx.doi.org/10.1016/j.ajpath.2014.01.031DOI Listing
May 2014

A positive feedback between p53 and miR-34 miRNAs mediates tumor suppression.

Genes Dev 2014 Mar 14;28(5):438-50. Epub 2014 Feb 14.

Molecular and Cell Biology Department, University of California at Berkeley, Berkeley, California 94705, USA;

As bona fide p53 transcriptional targets, miR-34 microRNAs (miRNAs) exhibit frequent alterations in many human tumor types and elicit multiple p53 downstream effects upon overexpression. Unexpectedly, miR-34 deletion alone fails to impair multiple p53-mediated tumor suppressor effects in mice, possibly due to the considerable redundancy in the p53 pathway. Here, we demonstrate that miR-34a represses HDM4, a potent negative regulator of p53, creating a positive feedback loop acting on p53. In a Kras-induced mouse lung cancer model, miR-34a deficiency alone does not exhibit a strong oncogenic effect. However, miR-34a deficiency strongly promotes tumorigenesis when p53 is haploinsufficient, suggesting that the defective p53-miR-34 feedback loop can enhance oncogenesis in a specific context. The importance of the p53/miR-34/HDM4 feedback loop is further confirmed by an inverse correlation between miR-34 and full-length HDM4 in human lung adenocarcinomas. In addition, human lung adenocarcinomas generate an elevated level of a short HDM4 isoform through alternative polyadenylation. This short HDM4 isoform lacks miR-34-binding sites in the 3' untranslated region (UTR), thereby evading miR-34 regulation to disable the p53-miR-34 positive feedback. Taken together, our results elucidated the intricate cross-talk between p53 and miR-34 miRNAs and revealed an important tumor suppressor effect generated by this positive feedback loop.
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http://dx.doi.org/10.1101/gad.233585.113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3950342PMC
March 2014

A microRNA miR-34a-regulated bimodal switch targets Notch in colon cancer stem cells.

Cell Stem Cell 2013 May;12(5):602-15

School of Electrical and Computer Engineering, Cornell University, Ithaca, NY 14853, USA.

microRNAs regulate developmental cell-fate decisions, tissue homeostasis, and oncogenesis in distinct ways relative to proteins. Here, we show that the tumor suppressor microRNA miR-34a is a cell-fate determinant in early-stage dividing colon cancer stem cells (CCSCs). In pair-cell assays, miR-34a distributes at high levels in differentiating progeny, whereas low levels of miR-34a demarcate self-renewing CCSCs. Moreover, miR-34a loss of function and gain of function alter the balance between self-renewal versus differentiation both in vitro and in vivo. Mechanistically, miR-34a sequesters Notch1 mRNA to generate a sharp threshold response where a bimodal Notch signal specifies the choice between self-renewal and differentiation. In contrast, the canonical cell-fate determinant Numb regulates Notch levels in a continuously graded manner. Altogether, our findings highlight a unique microRNA-regulated mechanism that converts noisy input into a toggle switch for robust cell-fate decisions in CCSCs.
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http://dx.doi.org/10.1016/j.stem.2013.03.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3646336PMC
May 2013

Spatial perturbation with synthetic protein scaffold reveals robustness of asymmetric cell division.

J Biomed Sci Eng 2013 Feb;6(2):134-143

Department of Biomedical Engineering, Cornell University, Ithaca, USA ; School of Electrical and Computer Engineering, Cornell University, Ithaca, USA.

Asymmetric cell division is an important mechanism for creating diversity in a cellular population. Stem cells commonly perform asymmetric division to generate both a daughter stem cell for self-renewal and a more differentiated daughter cell to populate the tissue. During asymmetric cell division, protein cell fate determinants asymmetrically localize to the opposite poles of a dividing cell to cause distinct cell fate. However, it remains unclear whether cell fate determination is robust to fluctuations and noise during this spatial allocation process. To answer this question, we engineered , a bacterial model for asymmetric division, to express synthetic scaffolds with modular protein interaction domains. These scaffolds perturbed the spatial distribution of the PleC-DivJ-DivK phospho-signaling network without changing their endogenous expression levels. Surprisingly, enforcing symmetrical distribution of these cell fate determinants did not result in symmetric daughter fate or any morphological defects. Further computational analysis suggested that PleC and DivJ form a robust phospho-switch that can tolerate high amount of spatial variation. This insight may shed light on the presence of similar phospho-switches in stem cell asymmetric division regulation. Overall, our study demonstrates that synthetic protein scaffolds can provide a useful tool to probe biological systems for better understanding of their operating principles.
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http://dx.doi.org/10.4236/jbise.2013.62017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4350780PMC
February 2013

Chemokine 25-induced signaling suppresses colon cancer invasion and metastasis.

J Clin Invest 2012 Sep 6;122(9):3184-96. Epub 2012 Aug 6.

Department of Medicine, Genetic Medicine, Weill Cornell Medical College, New York, New York, USA.

Chemotactic cytokines (chemokines) can help regulate tumor cell invasion and metastasis. Here, we show that chemokine 25 (CCL25) and its cognate receptor chemokine receptor 9 (CCR9) inhibit colorectal cancer (CRC) invasion and metastasis. We found that CCR9 protein expression levels were highest in colon adenomas and progressively decreased in invasive and metastatic CRCs. CCR9 was expressed in both primary tumor cell cultures and colon-cancer-initiating cell (CCIC) lines derived from early-stage CRCs but not from metastatic CRC. CCL25 stimulated cell proliferation by activating AKT signaling. In vivo, systemically injected CCR9+ early-stage CCICs led to the formation of orthotopic gastrointestinal xenograft tumors. Blocking CCR9 signaling inhibited CRC tumor formation in the native gastrointestinal CCL25+ microenvironment, while increasing extraintestinal tumor incidence. NOTCH signaling, which promotes CRC metastasis, increased extraintestinal tumor frequency by stimulating CCR9 proteasomal degradation. Overall, these data indicate that CCL25 and CCR9 regulate CRC progression and invasion and further demonstrate an appropriate in vivo experimental system to study CRC progression in the native colon microenvironment.
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http://dx.doi.org/10.1172/JCI62110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3428084PMC
September 2012

miR-34 miRNAs provide a barrier for somatic cell reprogramming.

Nat Cell Biol 2011 Oct 23;13(11):1353-60. Epub 2011 Oct 23.

Division of Cellular and Developmental Biology, Molecular and Cell Biology Department, University of California at Berkeley, Berkeley, California 94705, USA.

Somatic reprogramming induced by defined transcription factors is a low-efficiency process that is enhanced by p53 deficiency. So far, p21 is the only p53 target shown to contribute to p53 repression of iPSC (induced pluripotent stem cell) generation, indicating that additional p53 targets may regulate this process. Here, we demonstrate that miR-34 microRNAs (miRNAs), particularly miR-34a, exhibit p53-dependent induction during reprogramming. Mir34a deficiency in mice significantly increased reprogramming efficiency and kinetics, with miR-34a and p21 cooperatively regulating somatic reprogramming downstream of p53. Unlike p53 deficiency, which enhances reprogramming at the expense of iPSC pluripotency, genetic ablation of Mir34a promoted iPSC generation without compromising self-renewal or differentiation. Suppression of reprogramming by miR-34a was due, at least in part, to repression of pluripotency genes, including Nanog, Sox2 and Mycn (also known as N-Myc). This post-transcriptional gene repression by miR-34a also regulated iPSC differentiation kinetics. miR-34b and c similarly repressed reprogramming; and all three miR-34 miRNAs acted cooperatively in this process. Taken together, our findings identified miR-34 miRNAs as p53 targets that play an essential role in restraining somatic reprogramming.
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http://dx.doi.org/10.1038/ncb2366DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3541684PMC
October 2011

Influenza virus detection with pentabody-activated nanoparticles.

J Virol Methods 2010 Nov 30;169(2):282-9. Epub 2010 Jul 30.

National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Chaoyang District, 100101 Beijing, China.

A nanoparticle-based immunoassay was developed for the rapid and sensitive detection of avian influenza virus (AIV). In this method, AIV-specific pentabody (pVHH3B) was conjugated to magnetic nanoparticles (MNPs) and used to capture AIV. Gold nanoparticles (GNPs), labelled with the anti-AIV mouse monoclonal antibody 3C8, were used as a detector. In the presence of target samples, the pentabody pVHH3B enriched AIV on the MNPs. Thereafter, mAb 3C8-labelled GNPs (GNPs-mAb3C8) bound to MNPs via AIV and were separated using a magnetic field. GNPs in the complex catalyzed the oxidation of hydroquinone to quinone, and the OD value of quinone was measured. The developed assay displayed substantial signal change after incubation in an AIV sample in a concentration-dependent manner. The detection limit was 10 ng/ml, which is 10 times more sensitive than conventional double-antibody sandwich enzyme-linked immunosorbent assay (DAS-ELISA). In conclusion, by combining MNPs and a novel pentabody pVHH3B, this study provided a sensitive influenza viral detection assay that has the potential to become a rapid, sensitive and inexpensive diagnostic tool for infectious diseases.
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http://dx.doi.org/10.1016/j.jviromet.2010.07.024DOI Listing
November 2010

A novel antibody AA98 V(H)/L directed against CD146 efficiently inhibits angiogenesis.

Anticancer Res 2007 Nov-Dec;27(6B):4219-24

National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, PR China.

Background: An anti-CD146 monoclonal antibody, AA98, has been identified as an inhibitor of tumor angiogenesis. To overcome the inherent immunogenicity of murine antibody as well as to facilitate immunotoxin construction, a single chain AA98 V(H)/L with three-domain fragments was constructed and expressed in mammalian cells.

Materials And Methods: The genes of the AA98 heavy chain variable region and the light chain were linked with a modified 12 amino acid sequence that was derived from the heavy chain C(H)1 region, thus constituting the three-domain antibody V(H)/L. Soluble AA98 V(H)/L was produced by mammalian cells and purified by affinity chromatography. The specificity of AA98 V(H)/L for the CD146 molecule was detected by ELISA, immunofluorescence staining and flow cytometry.

Results: AA98 V(H)/L alone showed anti-angiogenic properties in a chicken chorioallantoic membrane (CAM) assay as the parent mAb AA98 did.

Conclusion: This newly generated AA98 V(H)/L antibody displays a therapeutic potential for tumor and other angiogenesis disorders, as well as providing a new strategy for antibody engineering for clinical applications.
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February 2008