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000286251 0247_ $$2doi$$a10.3389/fonc.2023.1223915
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000286251 1001_ $$aSong, Yurong$$b0
000286251 245__ $$aOrganoids and metastatic orthotopic mouse model for mismatch repair-deficient colorectal cancer.
000286251 260__ $$aLausanne$$bFrontiers Media$$c2023
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000286251 520__ $$aGenome integrity is essential for the survival of an organism. DNA mismatch repair (MMR) genes (e.g., MLH1, MSH2, MSH6, and PMS2) play a critical role in the DNA damage response pathway for genome integrity maintenance. Germline mutations of MMR genes can lead to Lynch syndrome or constitutional mismatch repair deficiency syndrome, resulting in an increased lifetime risk of developing cancer characterized by high microsatellite instability (MSI-H) and high mutation burden. Although immunotherapy has been approved for MMR-deficient (MMRd) cancer patients, the overall response rate needs to be improved and other management options are needed.To better understand the biology of MMRd cancers, elucidate the resistance mechanisms to immune modulation, and develop vaccines and therapeutic testing platforms for this high-risk population, we generated organoids and an orthotopic mouse model from intestine tumors developed in a Msh2-deficient mouse model, and followed with a detailed characterization.The organoids were shown to be of epithelial origin with stem cell features, to have a high frameshift mutation frequency with MSI-H and chromosome instability, and intra- and inter-tumor heterogeneity. An orthotopic model using intra-cecal implantation of tumor fragments derived from organoids showed progressive tumor growth, resulting in the development of adenocarcinomas mixed with mucinous features and distant metastasis in liver and lymph node.The established organoids with characteristics of MSI-H cancers can be used to study MMRd cancer biology. The orthotopic model, with its distant metastasis and expressing frameshift peptides, is suitable for evaluating the efficacy of neoantigen-based vaccines or anticancer drugs in combination with other therapies.
000286251 588__ $$aDataset connected to CrossRef, PubMed, , Journals: inrepo02.dkfz.de
000286251 650_7 $$2Other$$aLynch syndrome
000286251 650_7 $$2Other$$aMSH2
000286251 650_7 $$2Other$$achromosome instability
000286251 650_7 $$2Other$$acolorectal cancer
000286251 650_7 $$2Other$$amicrosatellite instability
000286251 650_7 $$2Other$$amismatch repair deficiency
000286251 650_7 $$2Other$$amouse model
000286251 650_7 $$2Other$$aorganoid
000286251 7001_ $$aKerr, Travis D$$b1
000286251 7001_ $$aSanders, Chelsea$$b2
000286251 7001_ $$aDai, Lisheng$$b3
000286251 7001_ $$aBaxter, Shaneen S$$b4
000286251 7001_ $$aSomerville, Brandon$$b5
000286251 7001_ $$aBaugher, Ryan N$$b6
000286251 7001_ $$aMellott, Stephanie D$$b7
000286251 7001_ $$aYoung, Todd B$$b8
000286251 7001_ $$aLawhorn, Heidi E$$b9
000286251 7001_ $$aPlona, Teri M$$b10
000286251 7001_ $$aXu, Bingfang$$b11
000286251 7001_ $$aWei, Lei$$b12
000286251 7001_ $$aHu, Qiang$$b13
000286251 7001_ $$aLiu, Song$$b14
000286251 7001_ $$aHutson, Alan$$b15
000286251 7001_ $$aKarim, Baktiar$$b16
000286251 7001_ $$aBurkett, Sandra$$b17
000286251 7001_ $$aDifilippantonio, Simone$$b18
000286251 7001_ $$aPinto, Ligia$$b19
000286251 7001_ $$aGebert, Johannes$$b20
000286251 7001_ $$aKloor, Matthias$$b21
000286251 7001_ $$aLipkin, Steven M$$b22
000286251 7001_ $$aSei, Shizuko$$b23
000286251 7001_ $$aShoemaker, Robert H$$b24
000286251 773__ $$0PERI:(DE-600)2649216-7$$a10.3389/fonc.2023.1223915$$gVol. 13, p. 1223915$$p1223915$$tFrontiers in oncology$$v13$$x2234-943X$$y2023
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