Name: patient-derived heterogeneous xenograft model of pancreatic cancer using zebrafish larvae as hosts for comparative drug assessment
Uploaded: 2019-04-30T14:00:00
Description: Watch this Scientific Journal Video about Patient-derived Heterogeneous Xenograft Model of Pancreatic Cancer Using Zebrafish Larvae as Hosts for Comparative Drug Assessment Video at JoVE.com

This work was supported by National Natural Science Foundation of China 81402582, Natural Science Foundation of Shanghai 12DZ2295100, 14YF1400600 and 18ZR1404500

All animal procedures were approved and followed the guidelines of the Animal Ethics Committee at Fudan University and all pancreatic cancer specimens were obtained from Fudan University Shanghai Cancer Center. Ethical approval was obtained from the FUSCC Ethics Committee, and written informed consent was obtained from each patient.
1. Preparing the Equipment for the Microinjection
<ol>
	<li>Preparing the injection plate.
	<ol>
		<li>Prepare a 50 mL solution of 1% agarose di...

<ol>
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A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Towards+Precision+Medicine+in+the+Clinic:+From+Biomarker+Discovery+to+Novel+Therapeutics.">Towards Precision Medicine in the Clinic: From Biomarker Discovery to Novel Therapeutics.</a> Trends in Pharmacological Sciences. 38 (1), 25-40 (2017).</li><li>Huang, L., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Ductal+pancreatic+cancer+modeling+and+drug+screening+using+human+pluripotent+stem+cell-+and+patient-derived+tumor+organoids.">Ductal pancreatic cancer modeling and drug screening using human pluripotent stem cell- and patient-derived tumor organoids.</a> Nature Medicine. 21 (11), 1364-1371 (2015).</li><li>Pauli, C., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Personalized+In+Vitro+and+In+Vivo+Cancer+Models+to+Guide+Precision+Medicine.">Personalized In Vitro and In Vivo Cancer Models to Guide Precision Medicine.</a> Cancer Discovery. 7 (5), 462-477 (2017).</li><li>Hidalgo, M., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Patient-derived+xenograft+models:+an+emerging+platform+for+translational+cancer+research.">Patient-derived xenograft models: an emerging platform for translational cancer research.</a> Cancer Discovery. 4 (9), 998-1013 (2014).</li><li>Jung, J., Seol, H. 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Both PDX and CDX models are vital platforms in the field of tumor biology22, and the critical step of a successful inter-species transplantation is to improve the survival of the xenograft. &#160;Recently, some studies have shown that transient expression of BCL2L1 (BCL-XL) or BCL2 may significantly improve the viability of human embryonic stem cells in mice hosts without affecting the cell identities and fates23,24</s...

Precision oncology aims to find the most beneficial therapeutic strategies for individual patient1. Currently, numerous preclinical models such as in vitro primary culture, in vitro organoid culture2, and patient-derived xenografts (PDX) in mice before or after organoid culture are proposed for diagnosis and to screen/assess the potential therapeutic choices3. PDX model generated by the injection of human primary cancer cells into immune-compromised mice, is one of the most promising tools for personalized drug screening in clinical oncology3,4. Unlike the cultured cell line in vitro, PDX models usually preserve the integrity and heterogeneity of the in vivo tumor environment, better mimicking the diversity and idiosyncratic characteristics of different tumor patients, and therefore, may predict the potential medical outcome of patients4. However, the generation of PDX models in mice requires high quality patient samples and months of time to gather sufficient cells and models for multi group experiments, and the cellular/genetic compositions of the xenograft may drift from those of the original patient&#8217;s biopsy. The success rate for establishing mice PDX model is also low, making it difficult to be broadly implemented in clinical practice. For the patients carrying rapidly progressed cancers like pancreatic cancer, they may not be able to obtain valuable information from the PDX experiments in time.&#160;
In the past few years, zebrafish has been reported to be potential hosts for not only CDX (cell-derived tumor xenograft) models, but also PDX models5,6,7,8,9,10. As a vertebrate model animal, zebrafish harbors sufficient similarities with mammals in both genetics and physiology, with two significant advantages: transparency and small in size11. Zebrafish is also highly fecundity, and hundreds of inbred larvae can be obtained within a few days from a single pair of adults12. Several studies have employed zebrafish to generate both transgenic and xenograft models of cancer diseases13,14. Compared to mice xenografts, zebrafish xenografts allow tracking at single cell resolution. A certain amount of human tissues is capable of generating hundreds of zebrafish PDX models (zPDXs), while may only be sufficient to generate a couple of mice PDX models15,16. Besides, the zebrafish larvae at 2-5 dpf already develop complete circulatory systems and metabolic organs such as liver and kidney, but not the immune system17, while the remaining yolk sac is a natural 3D medium, ideal for drug screening, drug resistance tests and tumor migration observations6,18,19,20,21.
With an ultimate attempt to use zPDX as a screening/testing platform for clinical use, here, we describe an optimized proposal for zPDX model of pancreatic cancer, which allows the in vivo candidate drug assessment within a short time using fewer cells at lower costs. Compared to the previous references about zPDX6,9,10, we introduced several optimizations to make the system more feasible and reliable for clinical personalized diagnosis: 1) pre-sorting different cell groups in the primary tumor tissues and stabilizing primary cells for one week before further experiments; 2) labeling the human cells and enhancing the cell viability in xenograft via lentivirus-based genetic modification; 3) optimizing the zebrafish culture condition in both nutriment supplements (glucose and glutamine) and temperature; 4) quantifying the drug responses of different cell types in a comparative manner. We also made changes to the injection solution by adding several supplementary materials. Altogether, those improvements provide the possibility to quickly generate a more patient-like xenograft in zebrafish hosts that can be used as a reliable tool to assess the response of candidate drugs.

<table>
	<tbody>
		<tr>
			<td>DMEM</td>
			<td>GIBCO</td>
			<td>C11995500BT</td>
			<td></td>
		</tr>
		<tr>
			<td>FBS</td>
			<td>Hyclone</td>
			<td>sv30087.03</td>
			<td></td>
		</tr>
		<tr>
			<td>Y-27632</td>
			<td>Cliniscience</td>
			<td>Y0503</td>
			<td>Rho kinase inhibitor</td>
		</tr>
		<tr>
			<td>Primocin</td>
			<td>invivogen</td>
			<td>ant-pm-1</td>
			<td>an antibiotic for primary cell cultures</td>
		</tr>
		<tr>
			<td>Putrescine dihydrochloride</td>
			<td>Sigma</td>
			<td>P5780</td>
			<td></td>
		</tr>
		<tr>
			<td>Nicotinamide&#160;</td>
			<td>Sigma</td>
			<td>N3376</td>
			<td></td>
		</tr>
		<tr>
			<td>penicillin streptomycin</td>
			<td>GIBCO</td>
			<td>15140122.00</td>
			<td></td>
		</tr>
		<tr>
			<td>phosphate buffer (PBS)</td>
			<td>GIBCO</td>
			<td>C10010500CP</td>
			<td></td>
		</tr>
		<tr>
			<td>HBSS&#160;</td>
			<td>GIBCO</td>
			<td>14170112.00</td>
			<td></td>
		</tr>
		<tr>
			<td>collagenase type IV</td>
			<td>GIBCO</td>
			<td>17104019.00</td>
			<td></td>
		</tr>
		<tr>
			<td>hyaluronidase</td>
			<td>Sigma</td>
			<td>H3884</td>
			<td></td>
		</tr>
		<tr>
			<td>Dnase&#8544;</td>
			<td>Sigma</td>
			<td>D5025</td>
			<td></td>
		</tr>
		<tr>
			<td>insulin</td>
			<td>Sigma</td>
			<td>I9278</td>
			<td></td>
		</tr>
		<tr>
			<td>b-FGF</td>
			<td>GIBCO</td>
			<td>PHG0264</td>
			<td></td>
		</tr>
		<tr>
			<td>EGF</td>
			<td>GIBCO</td>
			<td>PHG0314</td>
			<td></td>
		</tr>
		<tr>
			<td>pancreatic cancer fibroblasts inhibitor</td>
			<td>CHI Scientific</td>
			<td>FibrOUT</td>
			<td></td>
		</tr>
		<tr>
			<td>0.45 &#956;m sterile filter</td>
			<td>Millipore</td>
			<td>SLHV033RB</td>
			<td></td>
		</tr>
		<tr>
			<td>concentration column</td>
			<td>Millipore</td>
			<td>Millipore UFC910008</td>
			<td>Concentrate the virus</td>
		</tr>
		<tr>
			<td>polybrene&#160;</td>
			<td>Sigma</td>
			<td>H9268</td>
			<td></td>
		</tr>
		<tr>
			<td>Hyaluronic Acid Sodium Salt</td>
			<td>Sigma</td>
			<td>H7630</td>
			<td></td>
		</tr>
		<tr>
			<td>L-glutamine</td>
			<td>GIBCO</td>
			<td>21051024.00</td>
			<td></td>
		</tr>
		<tr>
			<td>gemcitabine</td>
			<td>Gemzan</td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>methylcellulose</td>
			<td>Sigma</td>
			<td>M0262</td>
			<td></td>
		</tr>
		<tr>
			<td>Navitoclax(ABT-263)</td>
			<td>Selleck</td>
			<td>S1001</td>
			<td>Bcl-xL inhibitor</td>
		</tr>
		<tr>
			<td>Equipment</td>
			<td></td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Microinjector</td>
			<td>NARISHIGE</td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>stereomicroscope</td>
			<td>OLYMPUS</td>
			<td>MVX10</td>
			<td></td>
		</tr>
		<tr>
			<td>Confocal Microscope</td>
			<td>LEICA</td>
			<td>SP8</td>
			<td>0.00</td>
		</tr>
	</tbody>
</table>

patient-derived heterogeneous xenograft model of pancreatic cancer using zebrafish larvae as hosts for comparative drug assessment

Patient-derived tumor xenograft (PDX) and cell-derived tumor xenograft (CDX) are important techniques for preclinical assessment, medication guidance and basic cancer researches. Generations of PDX models in traditional host mice are time-consuming and only working for a small proportion of samples. Recently, zebrafish PDX (zPDX) has emerged as a unique host system, with the characteristics of small-scale and high efficiency. Here, we describe an optimized methodology for generating a dual fluorescence-labeled tumor xenograft model for comparative chemotherapy assessment in zPDX models. Tumor cells and fibroblasts were enriched from freshly-harvested or frozen pancreatic cancer tissue at different culture conditions. Both cell groups were labeled by lentivirus expressing green or red fluorescent proteins, as well as an anti-apoptosis gene BCL2L1. The transfected cells were pre-mixed and co-injected into the 2 dpf larval zebrafish that were then bred in modified E3 medium at 32 &#176;C. The xenograft models were treated by chemotherapy drugs and/or BCL2L1 inhibitor, and the viabilities of both tumor cells and fibroblasts were investigated simultaneously. In summary, this protocol allows researchers to quickly generate a large amount of zPDX models with a heterogeneous tumor microenvironment and provides a longer observation window and a more precise quantitation in assessing the efficiency of drug candidates.

A schematized outline of the procedure is represented in Figure 1. In short, the primary cancer tissue cells were seeded into the complete medium after digestion with or without the addition of pancreatic cancer fibroblast inhibitors. Cancer cells and fibroblasts were enriched as two distinct populations that fibroblasts dominated without inhibitors, and cancer cell growth prevailed after the addition of inhibitors (Figure 2). Tw...

Watch this Scientific Journal Video about Patient-derived Heterogeneous Xenograft Model of Pancreatic Cancer Using Zebrafish Larvae as Hosts for Comparative Drug Assessment Video at JoVE.com

Patient-derived Heterogeneous Xenograft Model of Pancreatic Cancer Using Zebrafish Larvae as Hosts for Comparative Drug Assessment Video (Video) | JoVE

This protocol describes optimization procedures in a virus-based dual fluorescence-labeled tumor xenograft model using larval zebrafish as hosts. This heterogeneous xenograft model mimics the tissue composition of pancreatic cancer microenvironment in vivo and serves as a more precise tool for assessing drug responses in personalized zPDX (zebrafish patient-derived xenograft) models.

Patient-derived Heterogeneous Xenograft Model of Pancreatic Cancer Using Zebrafish Larvae as Hosts for Comparative Drug Assessment

Patient-derived tumor xenograft (PDX) and cell-derived tumor xenograft (CDX) are important techniques for preclinical assessment, medication guidance and ...

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