Extracellular Matrix in Synthetic Hydrogel-Based Prostate Cancer Organoids Regulate Therapeutic Response to EZH2 and DRD2 Inhibitors.
Extracellular Matrix in Synthetic Hydrogel-Based Prostate Cancer Organoids Regulate Therapeutic Response to EZH2 and DRD2 Inhibitors.
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DOI：
10.1002/adma.202100096
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发表时间：
2022-01
期刊：
影响因子：
--
通讯作者：
Singh A
中科院分区：
文献类型：
--
作者：
Mosquera MJ;Kim S;Bareja R;Fang Z;Cai S;Pan H;Asad M;Martin ML;Sigouros M;Rowdo FM;Ackermann S;Capuano J;Bernheim J;Cheung C;Doane A;Brady N;Singh R;Rickman DS;Prabhu V;Allen JE;Puca L;Coskun AF;Rubin MA;Beltran H;Mosquera JM;Elemento O;Singh A
在使用雄激素受体 (AR) 通路抑制剂治疗后，约 20% 的前列腺癌患者通过摆脱 AR 依赖性而取得进展。这些肿瘤经历表观遗传重编程，将去势抵抗性前列腺癌腺癌（CRPC-Adeno）转变为神经内分泌前列腺癌（CRPC-NEPC）。目前还没有针对 CRPC-NEPC 的靶向疗法，并且只有最小的类器官模型可以发现针对这些侵袭性肿瘤的新治疗靶点。在这里，结合使用患者肿瘤蛋白质组学、RNA 测序、空间组学和基于合成水凝胶的类器官，定义了调节 CRPC-NEPC 表型、转录组和表观遗传基础的假定细胞外基质 (ECM) 线索。肿瘤表达的 ECM 中的短期培养差异调节了 CRPC-NEPC 中的 DNA 甲基化和动员基因。 ECM 类型明显调节对表观遗传靶点和多巴胺受体 D2 (DRD2) 的小分子抑制剂的反应，后者是神经内分泌肿瘤中尚未得到充分研究的靶点。当用 DRD2 抑制剂治疗时，免疫功能低下小鼠体内源自患者的异种移植物显示出强烈的抗肿瘤反应。最后，我们证明了在耐药 ECM 条件下 CRPC-NEPC 的治疗反应可以通过首先使用表观遗传抑制剂进行细胞重编程，然后进行 DRD2 治疗来克服。合成类器官表明 ECM 在 CRPC-NEPC 靶向治疗的治疗反应中发挥调节作用，并使克服耐药性的治疗方法的发现成为可能。神经内分泌前列腺癌是表观遗传转化的肿瘤，目前尚无靶向治疗方法。通过结合转录组学、蛋白质组学、空间组学和对患者活检的显微镜检查，定义了细胞外基质肿瘤微环境。根据这些发现，开发了基于合成水凝胶的前列腺癌类器官，用于在特定的微环境条件下培养患者肿瘤细胞，从而发现新的治疗方法。
Following treatment with androgen receptor (AR) pathway inhibitors, ≈20% of prostate cancer patients progress by shedding their AR-dependence. These tumors undergo epigenetic reprogramming turning castration-resistant prostate cancer adenocarcinoma (CRPC-Adeno) into neuroendocrine prostate cancer (CRPC-NEPC). No targeted therapies are available for CRPC-NEPCs, and there are minimal organoid models to discover new therapeutic targets against these aggressive tumors. Here, using a combination of patient tumor proteomics, RNA sequencing, spatial-omics, and a synthetic hydrogel-based organoid, putative extracellular matrix (ECM) cues that regulate the phenotypic, transcriptomic, and epigenetic underpinnings of CRPC-NEPCs are defined. Short-term culture in tumor-expressed ECM differentially regulated DNA methylation and mobilized genes in CRPC-NEPCs. The ECM type distinctly regulates the response to small-molecule inhibitors of epigenetic targets and Dopamine Receptor D2 (DRD2), the latter being an understudied target in neuroendocrine tumors. In vivo patient-derived xenograft in immunocompromised mice showed strong anti-tumor response when treated with a DRD2 inhibitor. Finally, we demonstrate that therapeutic response in CRPC-NEPCs under drug-resistant ECM conditions can be overcome by first cellular reprogramming with epigenetic inhibitors, followed by DRD2 treatment. The synthetic organoids suggest the regulatory role of ECM in therapeutic response to targeted therapies in CRPC-NEPCs and enable the discovery of therapies to overcome resistance. Neuroendocrine prostate cancer is epigenetically transformed tumors for which no targeted therapies exist. Using a combination of transcriptomics, proteomics, spatial omics, and microscopy on patient biopsies, the extracellular matrix tumor microenvironment is defined. Informed by these findings, synthetic hydrogel-based prostate cancer organoids are developed to grow patient tumor cells under the defined microenvironment conditions, leading to the discovery of novel therapeutics.
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DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
影响因子：
14
作者：
Bellis, Susan L.
通讯作者：
Bellis, Susan L.
影响因子：
--
作者：
Arrillaga-Romany I;Chi AS;Allen JE;Oster W;Wen PY;Batchelor TT
通讯作者：
Batchelor TT
影响因子：
82.9
作者：
Beltran H;Prandi D;Mosquera JM;Benelli M;Puca L;Cyrta J;Marotz C;Giannopoulou E;Chakravarthi BV;Varambally S;Tomlins SA;Nanus DM;Tagawa ST;Van Allen EM;Elemento O;Sboner A;Garraway LA;Rubin MA;Demichelis F
通讯作者：
Demichelis F
DOI：
10.1073/pnas.0808932106
发表时间：
2009-01-13
影响因子：
11.1
作者：
Fischbach, Claudia;Kong, Hyun Joon;Mooney, David J.
通讯作者：
Mooney, David J.