Name: syngeneic mouse orthotopic allografts to model pancreatic cancer
Uploaded: 2022-10-04T15:00:00
Description: Watch this Scientific Journal Video about Syngeneic Mouse Orthotopic Allografts to Model Pancreatic Cancer at JoVE.com

我们要感谢TUM动物设施和核医学部成像核心设施Klinikum rechts der Isar提供的出色技术支持。这项研究得到了德国癌症联盟（DKTK）、德国研究协会（DFG SA 1374/4-2、DFG SA 1374/6-1、SFB 1321项目编号329628492 P06、P11和S01）的支持，威廉·桑德基金会（2020.174.1和2017.091.2）到D.S.，以及欧洲研究理事会（ERC CoG No. 648521，D.S.）的支持。

动物实验得到了慕尼黑工业大学和上巴伐利亚大学地方当局的机构动物护理和使用委员会（IACUCs）的批准。
1. 手术前要考虑的信息
<ol><li>在开始任何动物实验之前，确保地方当局批准动物方案和人员。</li>
	<li>选择受体小鼠。<ol><li>选择年龄相似的小鼠进行植入（年龄范围在2个月至4个月之间的C57Bl / 6J受体小鼠）。</li>
		<li>确保受体动物的性别和遗传背景与用于...

<ol>
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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=Genomics-driven+precision+medicine+for+advanced+pancreatic+cancer:+Early+results+from+the+COMPASS+trial.">Genomics-driven precision medicine for advanced pancreatic cancer: Early results from the COMPASS trial.</a> Clinical Cancer Research. 24 (6), 1344-1354 (2018).</li><li>Chan-Seng-Yue, 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=Transcription+phenotypes+of+pancreatic+cancer+are+driven+by+genomic+events+during+tumor+evolution.">Transcription phenotypes of pancreatic cancer are driven by genomic events during tumor evolution.</a> Nature Genetics. 52 (2), 231-240 (2020).</li><li>Kalimuthu, S. N., 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=Morphological+classification+of+pancreatic+ductal+adenocarcinoma+that+predicts+molecular+subtypes+and+correlates+with+clinical+outcome.">Morphological classification of pancreatic ductal adenocarcinoma that predicts molecular subtypes and correlates with clinical outcome.</a> Gut. 69 (2), 317-328 (2020).</li><li>Hayashi, A., 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=A+unifying+paradigm+for+transcriptional+heterogeneity+and+squamous+features+in+pancreatic+ductal+adenocarcinoma.">A unifying paradigm for transcriptional heterogeneity and squamous features in pancreatic ductal adenocarcinoma.</a> Nature Cancer. 1 (1), 59-74 (2020).</li><li>Mueller, S., 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=Evolutionary+routes+and+KRAS+dosage+define+pancreatic+cancer+phenotypes.">Evolutionary routes and KRAS dosage define pancreatic cancer phenotypes.</a> Nature. 554 (7690), 62-68 (2018).</li><li>Falcomata, 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=Selective+multi-kinase+inhibition+sensitizes+mesenchymal+pancreatic+cancer+to+immune+checkpoint+blockade+by+remodeling+the+tumor+microenvironment.">Selective multi-kinase inhibition sensitizes mesenchymal pancreatic cancer to immune checkpoint blockade by remodeling the tumor microenvironment.</a> Nature Cancer. 3 (3), 318-336 (2022).</li><li>Erstad, D. 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同系小鼠原位同种异体移植物因其成本效益、可重复性和相对简单的实验程序而代表了临床前研究的稳健模型13，15。这些模型不仅可以研究肿瘤 - 宿主相互作用，还可以保证在使用原代小鼠细胞培养物进行实验时保留其起源肿瘤的遗传异质性。
该协议为小鼠PDAC细胞培养物的原位植入胰腺提供了一种简单快速的程序。为了获得可重?...

最近，PDAC成为西方世界癌症相关死亡的第三大原因1。它导致所有癌症中最高的死亡率和~1%的10年总生存率，几十年来一直没有改变2。由于PDAC治疗缺乏进展，预计到未来十年，这种疾病将成为癌症相关死亡的第二大原因3。
PDAC肿瘤是复杂的实体，其特征在于由基质，血管，免疫和细胞外基质成分的异质组装组成的多样化肿瘤微环境（TME）4。TME成分的差异影响疾病预后和对治疗的反应4，5，6。事实上，许多研究表明，PDAC的基础样间充质亚型与高度免疫抑制的TME有关，并显示出生存率降低和对治疗缺乏反应7，8，9，10，11，12。因此，更深入地了解TME组成的差异以及这些特征如何影响肿瘤生物学仍然是开发分子精确疗法的重要因素。为了更好地了解这种复杂表型背后的生物学并确定能够克服PDAC的TME构成的屏障的治疗策略，体内模型是必不可少的。
任何癌症临床前模型系统的一个关键方面是它应该模仿人类表型，概括遗传异质性和结合构成TME的众多基质和免疫群体的环境。因此，在选择小鼠模型进行临床前研究时，必须考虑几个方面。为了研究肿瘤 - 免疫相互作用，可以将组织相容的癌细胞系注射到同源免疫功能小鼠中。在大多数情况下，这些被皮下注射到小鼠的侧腹，允许通过触诊或目视检查轻松监测肿瘤。然而，由此产生的模型并不模拟肿瘤细胞在其起源器官中的生长。因此，原位移植成为同种异体移植模型的黄金标准。
小鼠原位同种异体移植物有几个优点：它们具有成本效益，可以通过相对简单的程序生成，并产生具有已知分子组成的模型，以及可重复和可预测的肿瘤进展和表型。事实上，虽然患者来源的异种移植模型准确地代表了人类PDAC细胞的行为，但植入免疫缺陷小鼠以避免移植排斥的需要限制了对肿瘤 - 免疫和肿瘤 - 基质相互作用的分析，允许研究人员仅捕获这些肿瘤复杂性的部分图像。与基因工程小鼠模型（GEMMs）相比，PDAC的同源原位同种异体移植物在这方面也具有优势。GEMM准确地概括了人类PDAC肿瘤发生和PDAC患者中观察到的异质性。然而，由于这些特征，GEMM肿瘤在其基因组成，肿瘤进展，侵袭性，组织学分化和TME组成方面可以显示出高度差异。虽然这在某些研究中可能是一个优势，但它限制了基因型到表型的研究和PDAC表型的重点研究13。因此，小鼠原位同种异体移植物构成了在 体内进行肿瘤宿主和治疗研究的良好权衡和模型。本文概述了小鼠PDAC细胞进入小鼠胰腺的原位移植实验方案。

<table border="1" fo:keep-together.within-page="1" fo:keep-with-next.within-page="always">
	<tbody>
		<tr>
			<td>27 G cannula</td>
			<td>B.Braun</td>
			<td>08915992</td>
			<td></td>
		</tr>
		<tr>
			<td>Atipamezole (Antisedan 5 mg/mL)</td>
			<td>Orion Corporation</td>
			<td>23554.00.00</td>
			<td></td>
		</tr>
		<tr>
			<td>Autoclip Stainless Steel Wound Clips, 9 mm</td>
			<td>Braintree Scientific</td>
			<td>NC9334081</td>
			<td></td>
		</tr>
		<tr>
			<td>Dulbecco`s Modified Eagle Medium&#160;</td>
			<td>Sigma-Aldrich</td>
			<td>D5796-500ML</td>
			<td></td>
		</tr>
		<tr>
			<td>Eye cream (Bepanthen)</td>
			<td>Bayer Vital GmbH</td>
			<td>1578675</td>
			<td></td>
		</tr>
		<tr>
			<td>FBS</td>
			<td>Sigma-Aldrich</td>
			<td>S0615</td>
			<td></td>
		</tr>
		<tr>
			<td>Fentanyl (50 &#181;g/mL)</td>
			<td>Eurovet Animal Health BV</td>
			<td>9113473</td>
			<td></td>
		</tr>
		<tr>
			<td>Flumazenile (Flumazenil-hameln 0.1 mg/mL)</td>
			<td>Hameln pharma</td>
			<td>09611975</td>
			<td></td>
		</tr>
		<tr>
			<td>Medetomidine (Sedator 1 mg/mL)</td>
			<td>Eurovet Animal Health BV</td>
			<td>400926.00.00</td>
			<td></td>
		</tr>
		<tr>
			<td>Meloxicam (Metacam 5 mg/mL)</td>
			<td>Boehringer Ingelheim Vetmedica GmbH</td>
			<td>3937902</td>
			<td></td>
		</tr>
		<tr>
			<td>Microliter syringe</td>
			<td>Hamilton</td>
			<td>HT80908</td>
			<td></td>
		</tr>
		<tr>
			<td>Midazolam (5 mg/mL)</td>
			<td>Hexal</td>
			<td>00886423</td>
			<td></td>
		</tr>
		<tr>
			<td>NaCl</td>
			<td>B. Braun</td>
			<td>2737756</td>
			<td></td>
		</tr>
		<tr>
			<td>Naloxone (Naloxon-hameln 0.4 mg/mL)</td>
			<td>hameln pharma</td>
			<td>04464535</td>
			<td></td>
		</tr>
		<tr>
			<td>PBS</td>
			<td>Sigma-Aldrich</td>
			<td>P7059-1L</td>
			<td></td>
		</tr>
		<tr>
			<td>Penicillin-Streptomycin</td>
			<td>Sigma-Aldrich</td>
			<td>P4333-100ML</td>
			<td></td>
		</tr>
		<tr>
			<td>Suture (Ethilon)</td>
			<td>Ethicon</td>
			<td>9999034</td>
			<td></td>
		</tr>
		<tr>
			<td>TrypZean Solution 1x</td>
			<td>Sigma-Aldrich</td>
			<td>T3449</td>
			<td></td>
		</tr>
	</tbody>
</table>

syngeneic mouse orthotopic allografts to model pancreatic cancer

胰腺导管腺癌（PDAC）是一种非常复杂的疾病，其特征是由多种基质，免疫细胞，血管，神经和细胞外基质成分组成的异质性肿瘤微环境。多年来，已经开发了PDAC的不同小鼠模型，以解决其进展，转移潜力和表型异质性带来的挑战。与基因工程小鼠模型相比，PDAC的免疫功能正常的小鼠原位同种异体移植物因其快速且可重复的肿瘤进展而显示出良好的前景。此外，结合它们模拟在本土PDAC中观察到的生物学特征的能力，基于细胞系的原位同种异体移植小鼠模型能够进行大规模的 体内 实验。因此，这些模型广泛用于临床前研究，用于快速基因型表型和药物反应分析。该协议的目的是提供一种可重复且稳健的方法，以成功将原代小鼠PDAC细胞培养物注射到同系受体小鼠的胰腺中。除了技术细节外，还提供了在进行这些实验之前必须考虑的重要信息。

在大规模药物反应研究的背景下，我们使用上述方案成功植入了170多只小鼠（C75Bl6 / J受体小鼠，雄性和雌性小鼠性别匹配的PDAC细胞系注射），例如图1中的主要步骤12。在该协议中，我们原位植入了三种 KrasG12D 驱动的 PDAC 细胞系（PDAC 1 和 2：Ptf1aCre/+;LSL-克拉斯G12D/+;LSL-Trp53R172H/+， PDAC 3： ptf1acre/+;LSL-?...

Watch this Scientific Journal Video about Syngeneic Mouse Orthotopic Allografts to Model Pancreatic Cancer at JoVE.com

Syngeneic Mouse Orthotopic Allografts to Model Pancreatic Cancer

胰腺导管腺癌 （PDAC） 的同源小鼠原位同种异体移植物概括了疾病亚型的生物学、表型和治疗反应。由于其快速、可重复的肿瘤进展，它们被广泛用于临床前研究。在这里，我们展示了生成这些模型的常见做法，将同源鼠PDAC培养物注射到胰腺中。

同系小鼠原位同种异体移植物模拟胰腺癌

Pancreatic ductal adenocarcinoma (PDAC) is a very complex disease characterized by a heterogeneous tumor microenvironment made up of a diverse stroma, ...

该协议提供了可重复的，免疫能力正常的PDAC体内模型，适用于基因型，表型和药物反应研究。该技术的主要优点是它能够在同源生物肿瘤微环境中帮助研究肿瘤进展，同时保持实验的可重复性。演示该程序的是Stefanie Barthel和Chiara Falcomata，他们都来自我们的实验室。通过洗涤在带有磷酸盐缓冲盐水或PBS的T75培养瓶中生长的胰腺导管腺癌或PDAC细胞开始制备肿瘤细胞。然后加入0.5毫升胰蛋白酶5至10分钟，使其从烧瓶中分离。将分离的细胞重新悬浮在10毫升DMEM中，加入10%胎牛血清或FBS和0.1%青霉素链霉素，然后将细胞悬液转移到15毫升管中。将细胞悬液在200G下离心五分钟并吸出上清液。根据注射细胞所需的最终浓度，将细胞沉淀重新悬浮在不含添加剂的DMEM中。使用Neubauer室计数10微升细胞悬液中的细胞并计算可用细胞的数量。按照最终所需的浓度，将一毫升稀释的悬浮液转移到1.5毫升的管中。将管子放在旋转器上直到植入以防止细胞聚集。对于PDAC细胞的原位植入，在小鼠睡觉时将眼霜涂抹在镇静的小鼠身上。在剃除镇静小鼠的左外腹之前检查足够的镇静剂。将右侧的鼠标放在无菌加热垫上，并将腿贴在表面上。戴上新手套并进行消毒。使用手术剪刀，在脾脏突出的左胁纵向切开约1厘米的皮肤和皮下脂肪组织。使用剪刀和镊子将皮肤与腹膜分开，以便更容易进入腹膜。在用一厘米的纵向切口打开脾脏位置的腹膜之前，更换一把剪刀。在使用钝的细镊子活动脾脏和附着的胰腺时，确保器官不附着在其他组织上。还要检查供应血管，以避免在处理胰腺时伤害血管或周围组织。小心地将胰腺从切口中拉出，以便更容易地进入器官的尾巴，并观察胰腺之后的脾脏。确保器官在注射过程中没有折叠，并且器官的囊在针刺部位保持张力，以避免溢出。瞄准可见血管之间的一块胰腺组织，以尽量减少穿刺或注射血管的风险。使用惯用手，沿着器官的纵轴小心地用27号套管和50微升注射器穿透器官的胶囊。将含有2， 500个细胞的20微升悬浮液注射到胰腺尾部区域后，保持胰腺和插入的注射器静止约一分钟，以避免溢出肿瘤细胞。然后，从注射部位取出针头。接下来，小心地重新排列腹部内的器官，不要伤害组织，以避免溢出细胞。通过将一毫升0.9%氯化钠倒入器官上来避免器官粘连。使用简单的间断缝合技术缝合腹膜后，使用两到三个九毫米的不锈钢缠绕夹闭合皮肤。然后根据小鼠体重皮下注射AFN，用咪达唑仑，美地托马定和芬太尼或MMF拮抗镇静剂。完成后，将鼠标放入 37 摄氏度的加热室中，直到它唤醒并完全活动。将活动小鼠放回其原始笼子中，并通过检查皮毛、肤色和活动来监测小鼠的健康状况，并在手术后三到四个小时重复此操作。在植入小鼠的MRI中，PDAC细胞的植入最早在手术后约7天进行腹部触诊，具体取决于注射的细胞数量以及接种细胞系的侵袭性和生长特征。由此产生的植入小鼠的存活率取决于细胞系的肿瘤细胞内在特征。成功的胰腺内注射导致小鼠胰腺中肿瘤全面发展。相反，由于注射非活细胞、排斥植入细胞或注射细胞数量不足，植入不成功导致胰腺肿瘤的缺失。切记注射时注意不要溢出任何细胞，也不要伤害任何周围组织，以防止细胞在腹部内扩散。按照该程序，可以在免疫活性小鼠中进行体内研究，如临床前药物反应研究，然后进行例如事实、测序或组织学分析以调查肿瘤宿主相互作用。

Research

JoVE Journal

Cancer Research

Fluorescent Orthotopic Mouse Model of Pancreatic Cancer

胰腺癌的荧光原位小鼠模型

Pancreatic cancer remains one of the cancers for which survival has not improved substantially in the last few decades. Only 7% of diagnosed patients will ...

科研

癌症研究

A Syngeneic Mouse Model of Metastatic Renal Cell Carcinoma for Quantitative and Longitudinal Assessment of Preclinical Therapies

转移性的型号同源小鼠肾细胞癌的临床前疗法的定量和纵向评估

Renal cell carcinoma (RCC) affects &#62; 60,000 people in the United States annually, and ~ 30% of RCC patients have multiple metastases at the time of ...

Isolation of Circulating Tumor Cells in an Orthotopic Mouse Model of Colorectal Cancer

在直肠癌原位小鼠模型中循环肿瘤细胞的分离

Despite the advantages of easy applicability and cost-effectiveness, subcutaneous mouse models have severe limitations and do not accurately simulate ...

A Syngeneic Pancreatic Cancer Mouse Model to Study the Effects of Irreversible Electroporation

自体胰腺癌小鼠模型研究不可逆电穿孔的影响

Pancreatic cancer (PC), a disease which kills approximately 40,000 patients each year in the US, has successfully evaded several therapeutic approaches ...

A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer

雄激素依赖性和去势抗性前列腺癌的荧光自体小鼠模型

Orthotopic tumor modeling is a valuable tool for pre-clinical prostate cancer research, as it has multiple advantages over both subcutaneous and ...

Immunophenotyping of Orthotopic Homograft (Syngeneic) of Murine Primary KPC Pancreatic Ductal Adenocarcinoma by Flow Cytometry

Immunophenotyping of Orthotopic Homograft Syngeneic of Murine Primary KPC Pancreatic Ductal Adenocarcinoma by Flow Cytometry

流式细胞术对小鼠原发性胰腺导管腺癌原位同种异体 (自体) 免疫分型的研究

Homograft (syngeneic) tumors are the workhorse of today&#39;s immuno-oncology (I/O) preclinical research. The tumor microenvironment (TME), particularly ...

Orthotopic Transplantation of Syngeneic Lung Adenocarcinoma Cells to Study PD-L1 Expression

合成肺腺癌细胞原位移植研究 pd-l1 表达

The use of mouse models is indispensable for studying the pathophysiology of various diseases. With respect to lung cancer, several models are available, ...

A Syngeneic Mouse B-Cell Lymphoma Model for Pre-Clinical Evaluation of CD19 CAR T Cells

同源小鼠 B 细胞淋巴瘤模型对 CD19 轿车 T 细胞的临床前评价

The astonishing clinical success of CD19 chimeric antigen receptor (CAR) T-cell therapy has led to the approval of two second generation chimeric antigen ...

Studying Triple Negative Breast Cancer Using Orthotopic Breast Cancer Model

研究使用正交乳腺癌模型的三阴性乳腺癌

Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype with limited therapeutic options. When compared to patients with less ...

Ultrasound-Guided Orthotopic Implantation of Murine Pancreatic Ductal Adenocarcinoma

毛尿胰腺腺腺腺癌超声引导正射植入

The recent success of immune checkpoint blockade in melanoma and lung adenocarcinoma has galvanized the field of immuno-oncology as well as revealed the ...