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Integrative analysis of non-small cell lung cancer patient-derived xenografts identifies unique proteotypes associated with patient outcomes

ABSTRACT: Integrative analysis of non-small cell lung cancer patient-derived xenografts identifies unique proteotypes associated with patient outcomes

PROVIDER: PRJNA702550 | ENA |

REPOSITORIES: ENA

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Integrative analysis of non-small cell lung cancer patient-derived xenografts identifies unique proteotypes associated with patient outcomes [HT12v4]

Project description:Integrative analysis of non-small cell lung cancer patient-derived xenografts identifies unique proteotypes associated with patient outcomes [HT12v4]

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Integrative analysis of non-small cell lung cancer patient-derived xenografts identifies unique proteotypes associated with patient outcomes [WG-DASL]

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Integrative analysis of non-small cell lung cancer patient-derived xenografts identifies unique proteotypes associated with patient outcomes [HT12v4]

Project description:Non-small cell lung cancer (NSCLC) death rates exceed the next 3 prevalent cancers combined; however, most NSCLC tumors lack actionable mutations. Recent studies of NSCLC and other cancers revealed profound proteome remodelling with prognostic impact that is not fully predicted by DNA or RNA analyses. These revelations portend proteome-based cancer classification and treatment. This will require model systems that recapitulate tumor proteomes and phenotypes. A subset (~35%) of the most aggressive NSCLC can form a patient-derived xenograft (PDX). We generated 137 PDX models of aggressive NSCLC, which represent the histological, genome, transcriptome, and DNA methylation features and proteome remodelling of primary NSCLC. The models indicate 3 lung adenocarcinoma and 2 squamous cell carcinoma proteotypes that are associated with different patient outcomes, protein-phosphotyrosine profiles, candidate targets, and in adenocarcinoma, distinct stromal immune features. The PDX resource will foster proteome-directed stratification and development of new treatments for aggressive NSCLC.

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Patient-derived Human Breast Cancer Xenografts

Project description:Breast cancer research is hampered by difficulties in obtaining and studying primary human breast tissue, and by the lack of in vivo preclinical models that reflect patient tumor biology accurately. To overcome these limitations, we propagated a cohort of human breast tumors grown in the epithelium-free mammary fat pad of SCID/Beige and NOD/SCID/IL2γ-receptor null (NSG) mice, under a series of transplant conditions. Both models yielded stably transplantable xenografts at comparably high rates (~23% and ~19%, respectively). Of the conditions tested, xenograft take rate was highest in the presence of a low-dose estradiol pellet. Overall, 32 stably transplantable xenograft lines were established, representing unique 25 patients. Most tumors yielding xenografts were “triple-negative” (ER-PR-HER2+) (n=19). However, we established lines from three ER-PR-HER2+ tumors, one ER+PR-HER2-, one ER+PR+HER2- and one “triple-positive” (ER+PR+HER2+) tumor. Serially passaged xenografts show biological consistency with the tumor of origin, are phenotypic stability across multiple transplant generations at the histological, transcriptomic, proteomic, and genomic levels, and show comparable treatment responses. Xenografts representing 12 patients, including two ER+ lines, showed metastasis to the mouse lung. These models thus serve as a renewable, quality-controlled tissue resource for preclinical studies investigating treatment response and metastasis. The study was designed to determine how stable patient-derived xenografts are across multiple transplant generations in mice, and to determine how closely xenografts established with pre-treatment samples cluster with xenografts established with post-treatment samples. Overall, pre-treatment and post-treatment samples derived from the same patient cluster together, and multiple transplant generations of xenografts derived from an individual patient cluster together.

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