Publications by authors named "Huanhuan Joyce Chen"

19 Publications

  • Page 1 of 1

Clinical analysis and pluripotent stem cells-based model reveal possible impacts of ACE2 and lung progenitor cells on infants vulnerable to COVID-19.

Theranostics 2021 1;11(5):2170-2181. Epub 2021 Jan 1.

Department of Medicine, the University of Hong Kong, Hong Kong SAR, China.

An increasing number of children with severe coronavirus disease 2019 (COVID-19) is being reported, yet the spectrum of disease severity and expression patterns of angiotensin-converting enzyme 2 (ACE2) in children at different developmental stages are largely unknow. We analysed clinical features in a cohort of 173 children with COVID-19 (0-15 yrs.-old) between January 22, 2020 and March 15, 2020. We systematically examined the expression and distribution of in different developmental stages of children by using a combination of children's lung biopsies, pluripotent stem cell-derived lung cells, RNA-sequencing profiles, and SARS-CoV-2 pseudoviral infections. It revealed that infants (< 1yrs.-old), with a weaker potency of immune response, are more vulnerable to develop pneumonia whereas older children (> 1 yrs.-old) are more resistant to lung injury. The expression levels of however do not vary by age in children's lung. is notably expressed not only in Alveolar Type II (AT II) cells, but also in positive lung progenitor cells detected in both pluripotent stem cell derivatives and infants' lungs. The cells are readily infected by SARS-CoV-2 pseudovirus and the numbers of the double positive cells are significantly decreased in older children. Infants (< 1 yrs.-old) with SARS-CoV-2 infection are more vulnerable to lung injuries. expression in multiple types of lung cells including positive progenitor cells, in cooperation with an unestablished immune system, could be risk factors contributing to vulnerability of infants with COVID-19. There is a need to continue monitoring lung development in young children who have recovered from SARS-CoV-2 infection.
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http://dx.doi.org/10.7150/thno.53136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7797681PMC
February 2021

Distinct disease severity between children and older adults with COVID-19: Impacts of ACE2 expression, distribution, and lung progenitor cells.

Clin Infect Dis 2021 Jan 3. Epub 2021 Jan 3.

Prenatal Diagnostic Centre and Cord Blood Bank; Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China.

Background: Children and older adults with coronavirus disease 2019 (COVID-19) display a distinct spectrum of disease severity yet the risk factors aren't well understood. We sought to examine the expression pattern of angiotensin-converting enzyme 2 (ACE2), the cell-entry receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and the role of lung progenitor cells in children and older patients.

Methods: We retrospectively analysed clinical features in a cohort of 299 patients with COVID-19. The expression and distribution of ACE2 and lung progenitor cells were systematically examined using a combination of public single-cell RNA-seq datasets, lung biopsies, and ex vivo infection of lung tissues with SARS-CoV-2 pseudovirus in children and older adults. We also followed up patients who had recovered from COVID-19.

Results: Compared with children, older patients (> 50 yrs.) were more likely to develop into serious pneumonia with reduced lymphocytes and aberrant inflammatory response (p = 0.001). The expression level of ACE2 and lung progenitor cell markers were generally decreased in older patients. Notably, ACE2 positive cells were mainly distributed in the alveolar region, including SFTPC positive cells, but rarely in airway regions in the older adults (p < 0.01). The follow-up of discharged patients revealed a prolonged recovery from pneumonia in the older (p < 0.025).

Conclusion: Compared to children, ACE2 positive cells are generally decreased in older adults and mainly presented in the lower pulmonary tract. The lung progenitor cells are also decreased. These risk factors may impact disease severity and recovery from pneumonia caused by SARS-Cov-2 infection in older patients.
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http://dx.doi.org/10.1093/cid/ciaa1911DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7799282PMC
January 2021

Human pluripotent stem cell-derived lung organoids: Potential applications in development and disease modeling.

Wiley Interdiscip Rev Dev Biol 2020 Nov 3:e399. Epub 2020 Nov 3.

Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.

The pulmonary system is comprised of two main compartments, airways and alveolar space. Their tissue and cellular complexity ensure lung function and protection from external agents, for example, virus. Two-dimensional (2D) in vitro systems and animal models have been largely employed to elucidate the molecular mechanisms underlying human lung development, physiology, and pathogenesis. However, neither of these models accurately recapitulate the human lung environment and cellular crosstalk. More recently, human-derived three-dimensional (3D) models have been generated allowing for a deeper understanding of cell-to-cell communication. However, the availability and accessibility of primary human cell sources from which generate the 2D and 3D models may be limited. In the past few years, protocols have been developed to successfully employ human pluripotent stem cells (hPSCs) and differentiate them toward pulmonary fate in vitro. In the present review, we discuss the advantages and pitfalls of hPSC-derived lung 2D and 3D models, including the main characteristics and potentials for these models and their current and future applications for modeling development and diseases. Lung organoids currently represent the closest model to the human pulmonary system. We further focus on the applications of lung organoids for the study of human diseases such as pulmonary fibrosis, infectious diseases, and lung cancer. Finally, we discuss the present limitations and potential future applications of 3D lung organoids. This article is categorized under: Adult Stem Cells, Tissue Renewal, and Regeneration > Stem Cells and Disease Adult Stem Cells, Tissue Renewal, and Regeneration > Stem Cell Differentiation and Reversion.
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http://dx.doi.org/10.1002/wdev.399DOI Listing
November 2020

Identification of SARS-CoV-2 inhibitors using lung and colonic organoids.

Nature 2021 01 28;589(7841):270-275. Epub 2020 Oct 28.

Department of Surgery, Weill Cornell Medicine, New York, NY, USA.

There is an urgent need to create novel models using human disease-relevant cells to study severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) biology and to facilitate drug screening. Here, as SARS-CoV-2 primarily infects the respiratory tract, we developed a lung organoid model using human pluripotent stem cells (hPSC-LOs). The hPSC-LOs (particularly alveolar type-II-like cells) are permissive to SARS-CoV-2 infection, and showed robust induction of chemokines following SARS-CoV-2 infection, similar to what is seen in patients with COVID-19. Nearly 25% of these patients also have gastrointestinal manifestations, which are associated with worse COVID-19 outcomes. We therefore also generated complementary hPSC-derived colonic organoids (hPSC-COs) to explore the response of colonic cells to SARS-CoV-2 infection. We found that multiple colonic cell types, especially enterocytes, express ACE2 and are permissive to SARS-CoV-2 infection. Using hPSC-LOs, we performed a high-throughput screen of drugs approved by the FDA (US Food and Drug Administration) and identified entry inhibitors of SARS-CoV-2, including imatinib, mycophenolic acid and quinacrine dihydrochloride. Treatment at physiologically relevant levels of these drugs significantly inhibited SARS-CoV-2 infection of both hPSC-LOs and hPSC-COs. Together, these data demonstrate that hPSC-LOs and hPSC-COs infected by SARS-CoV-2 can serve as disease models to study SARS-CoV-2 infection and provide a valuable resource for drug screening to identify candidate COVID-19 therapeutics.
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http://dx.doi.org/10.1038/s41586-020-2901-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8034380PMC
January 2021

Modeling COVID-19 with Human Pluripotent Stem Cell-Derived Cells Reveals Synergistic Effects of Anti-inflammatory Macrophages with ACE2 Inhibition Against SARS-CoV-2.

Res Sq 2020 Aug 20. Epub 2020 Aug 20.

Dysfunctional immune responses contribute critically to the progression of Coronavirus Disease-2019 (COVID-19) from mild to severe stages including fatality, with pro-inflammatory macrophages as one of the main mediators of lung hyper-inflammation. Therefore, there is an urgent need to better understand the interactions among SARS-CoV-2 permissive cells, macrophage, and the SARS-CoV-2 virus, thereby offering important insights into new therapeutic strategies. Here, we used directed differentiation of human pluripotent stem cells (hPSCs) to establish a lung and macrophage co-culture system and model the host-pathogen interaction and immune response caused by SARS-CoV-2 infection. Among the hPSC-derived lung cells, alveolar type II and ciliated cells are the major cell populations expressing the viral receptor ACE2 and co-effector TMPRSS2, and both were highly permissive to viral infection. We found that alternatively polarized macrophages (M2) and classically polarized macrophages (M1) had similar inhibitory effects on SARS-CoV-2 infection. However, only M1 macrophages significantly up-regulated inflammatory factors including IL-6 and IL-18, inhibiting growth and enhancing apoptosis of lung cells. Inhibiting viral entry into target cells using an ACE2 blocking antibody enhanced the activity of M2 macrophages, resulting in nearly complete clearance of virus and protection of lung cells. These results suggest a potential therapeutic strategy, in that by blocking viral entrance to target cells while boosting anti-inflammatory action of macrophages at an early stage of infection, M2 macrophages can eliminate SARS-CoV-2, while sparing lung cells and suppressing the dysfunctional hyper-inflammatory response mediated by M1 macrophages.
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http://dx.doi.org/10.21203/rs.3.rs-62758/v1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7444287PMC
August 2020

A Human Pluripotent Stem Cell-based Platform to Study SARS-CoV-2 Tropism and Model Virus Infection in Human Cells and Organoids.

Cell Stem Cell 2020 07 19;27(1):125-136.e7. Epub 2020 Jun 19.

The Pritzker School of Molecular Engineering, the Ben May Department for Cancer Research, the University of Chicago, IL, USA.

SARS-CoV-2 has caused the COVID-19 pandemic. There is an urgent need for physiological models to study SARS-CoV-2 infection using human disease-relevant cells. COVID-19 pathophysiology includes respiratory failure but involves other organ systems including gut, liver, heart, and pancreas. We present an experimental platform comprised of cell and organoid derivatives from human pluripotent stem cells (hPSCs). A Spike-enabled pseudo-entry virus infects pancreatic endocrine cells, liver organoids, cardiomyocytes, and dopaminergic neurons. Recent clinical studies show a strong association with COVID-19 and diabetes. We find that human pancreatic beta cells and liver organoids are highly permissive to SARS-CoV-2 infection, further validated using adult primary human islets and adult hepatocyte and cholangiocyte organoids. SARS-CoV-2 infection caused striking expression of chemokines, as also seen in primary human COVID-19 pulmonary autopsy samples. hPSC-derived cells/organoids provide valuable models for understanding the cellular responses of human tissues to SARS-CoV-2 infection and for disease modeling of COVID-19.
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http://dx.doi.org/10.1016/j.stem.2020.06.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7303620PMC
July 2020

Identification of Candidate COVID-19 Therapeutics using hPSC-derived Lung Organoids.

bioRxiv 2020 May 5. Epub 2020 May 5.

The SARS-CoV-2 virus has caused already over 3.5 million COVID-19 cases and 250,000 deaths globally. There is an urgent need to create novel models to study SARS-CoV-2 using human disease-relevant cells to understand key features of virus biology and facilitate drug screening. As primary SARS-CoV-2 infection is respiratory-based, we developed a lung organoid model using human pluripotent stem cells (hPSCs) that could be adapted for drug screens. The lung organoids, particularly aveolar type II cells, express ACE2 and are permissive to SARS-CoV-2 infection. Transcriptomic analysis following SARS-CoV-2 infection revealed a robust induction of chemokines and cytokines with little type I/III interferon signaling, similar to that observed amongst human COVID-19 pulmonary infections. We performed a high throughput screen using hPSC-derived lung organoids and identified FDA-approved drug candidates, including imatinib and mycophenolic acid, as inhibitors of SARS-CoV-2 entry. Pre- or post-treatment with these drugs at physiologically relevant levels decreased SARS-CoV-2 infection of hPSC-derived lung organoids. Together, these data demonstrate that hPSC-derived lung cells infected by SARS-CoV-2 can model human COVID-19 disease and provide a valuable resource to screen for FDA-approved drugs that might be repurposed and should be considered for COVID-19 clinical trials.
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http://dx.doi.org/10.1101/2020.05.05.079095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7263550PMC
May 2020

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

Generation of pulmonary neuroendocrine cells and SCLC-like tumors from human embryonic stem cells.

J Exp Med 2019 03 8;216(3):674-687. Epub 2019 Feb 8.

Meyer Cancer Center, Weill Cornell Medicine, New York, NY

Cancer models based on cells derived from human embryonic stem cells (hESCs) may reveal why certain constellations of genetic changes drive carcinogenesis in specialized lineages. Here we demonstrate that inhibition of NOTCH signaling induces up to 10% of lung progenitor cells to form pulmonary neuroendocrine cells (PNECs), putative precursors to small cell lung cancers (SCLCs), and we can increase PNECs by reducing levels of retinoblastoma (RB) proteins with inhibitory RNA. Reducing levels of TP53 protein or expressing mutant or genes did not induce or expand PNECs, but tumors resembling early-stage SCLC grew in immunodeficient mice after subcutaneous injection of PNEC-containing cultures in which expression of both and was blocked. Single-cell RNA profiles of PNECs are heterogeneous; when RB levels are reduced, the profiles resemble those from early-stage SCLC; and when both RB and TP53 levels are reduced, the transcriptome is enriched with cell cycle-specific RNAs. Our findings suggest that genetic manipulation of hESC-derived pulmonary cells will enable studies of this recalcitrant cancer.
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http://dx.doi.org/10.1084/jem.20181155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6400536PMC
March 2019

Engineering a Bioartificial Human Colon Model Through Decellularization and Recellularization.

Methods Mol Biol 2019 ;1907:91-102

Department of Biomedical Engineering, Cornell University, Ithaca, NY, USA.

The tissue engineering method of decellularization and recellularization has been successfully used in a variety of regenerative medicine applications. The protocols used to de/recellularize various organs and tissues are largely different. Here we describe a method to effectively engineer a bioartificial colon by completely removing original cells from human intestinal tissues followed by repopulating the acellular tissue matrix with cell cultures. This method provides a novel approach for human intestinal regeneration and can be used to identify potential cancer driver genes.
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http://dx.doi.org/10.1007/978-1-4939-8967-6_7DOI Listing
July 2019

A pumpless body-on-a-chip model using a primary culture of human intestinal cells and a 3D culture of liver cells.

Lab Chip 2018 07;18(14):2036-2046

Department of Biomedical Engineering, 115 Weill Hall, Cornell University, USA.

We describe an expanded modular gastrointestinal (GI) tract-liver system by co-culture of primary human intestinal epithelial cells (hIECs) and 3D liver mimic. The two organ body-on-chip design consisted of GI and liver tissue compartments that were connected by fluidic medium flow driven via gravity. The hIECs and HepG2 C3A liver cells in the co-culture system maintained high viability for at least 14 days in which hIECs differentiated into major cell types found in native human intestinal epithelium and the HepG2 C3A cells cultured on 3D polymer scaffold formed a liver micro-lobe like structure. Moreover, the hIECs formed a monolayer on polycarbonate membranes with a tight junction and authentic TEER values of approximately 250 Ω cm2 for the native gut. The hIEC permeability was compared to a conventional permeability model using Caco-2 cell response for drug absorption by measuring the uptake of propranolol, mannitol and caffeine. Metabolic rates (urea or albumin production) of the cells in the co-culture GI-liver system were comparable to those of HepG2 C3A cells in a single-organ fluidic culture system, while induced CYP activities were significantly increased in the co-culture GI tract-liver system compared to the single-organ fluidic culture system. These results demonstrated potential of the low-cost microphysiological GI-liver model for preclinical studies to predict human response.
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http://dx.doi.org/10.1039/c8lc00111aDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6039263PMC
July 2018

Colonic organoids derived from human induced pluripotent stem cells for modeling colorectal cancer and drug testing.

Nat Med 2017 Jul 19;23(7):878-884. Epub 2017 Jun 19.

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

With the goal of modeling human disease of the large intestine, we sought to develop an effective protocol for deriving colonic organoids (COs) from differentiated human embryonic stem cells (hESCs) or induced pluripotent stem cells (iPSCs). Extensive gene and immunohistochemical profiling confirmed that the derived COs represent colon rather than small intestine, containing stem cells, transit-amplifying cells, and the expected spectrum of differentiated cells, including goblet and endocrine cells. We applied this strategy to iPSCs derived from patients with familial adenomatous polyposis (FAP-iPSCs) harboring germline mutations in the WNT-signaling-pathway-regulator gene encoding APC, and we generated COs that exhibit enhanced WNT activity and increased epithelial cell proliferation, which we used as a platform for drug testing. Two potential compounds, XAV939 and rapamycin, decreased proliferation in FAP-COs, but also affected cell proliferation in wild-type COs, which thus limits their therapeutic application. By contrast, we found that geneticin, a ribosome-binding antibiotic with translational 'read-through' activity, efficiently targeted abnormal WNT activity and restored normal proliferation specifically in APC-mutant FAP-COs. These studies provide an efficient strategy for deriving human COs, which can be used in disease modeling and drug discovery for colorectal disease.
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http://dx.doi.org/10.1038/nm.4355DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6055224PMC
July 2017

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

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

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

Biomimetic tissue-engineered systems for advancing cancer research: NCI Strategic Workshop report.

Cancer Res 2014 Oct 5;74(19):5359-63. Epub 2014 Aug 5.

Division of Cancer Biology, National Cancer Institute, Rockville, Maryland.

Advanced technologies and biomaterials developed for tissue engineering and regenerative medicine present tractable biomimetic systems with potential applications for cancer research. Recently, the National Cancer Institute convened a Strategic Workshop to explore the use of tissue biomanufacturing for development of dynamic, physiologically relevant in vitro and ex vivo biomimetic systems to study cancer biology and drug efficacy. The workshop provided a forum to identify current progress, research gaps, and necessary steps to advance the field. Opportunities discussed included development of tumor biomimetic systems with an emphasis on reproducibility and validation of new biomimetic tumor models, as described in this report.
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http://dx.doi.org/10.1158/0008-5472.CAN-14-1706DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4184963PMC
October 2014

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