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Stepwise-edited, human melanoma models reveal mutations' effect on tumor and microenvironment.

ABSTRACT: Establishing causal relationships between genetic alterations of human cancers and specific phenotypes of malignancy remains a challenge. We sequentially introduced mutations into healthy human melanocytes in up to five genes spanning six commonly disrupted melanoma pathways, forming nine genetically distinct cellular models of melanoma. We connected mutant melanocyte genotypes to malignant cell expression programs in vitro and in vivo, replicative immortality, malignancy, rapid tumor growth, pigmentation, metastasis, and histopathology. Mutations in malignant cells also affected tumor microenvironment composition and cell states. Our melanoma models shared genotype-associated expression programs with patient melanomas, and a deep learning model showed that these models partially recapitulated genotype-associated histopathological features as well. Thus, a progressive series of genome-edited human cancer models can causally connect genotypes carrying multiple mutations to phenotype.

SUBMITTER: Hodis E

PROVIDER: S-EPMC9427199 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

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Stepwise-edited, human melanoma models reveal mutations' effect on tumor and microenvironment.

Hodis Eran E Torlai Triglia Elena E Kwon John Y H JYH Biancalani Tommaso T Zakka Labib R LR Parkar Saurabh S Hütter Jan-Christian JC Buffoni Lorenzo L Delorey Toni M TM Phillips Devan D Dionne Danielle D Nguyen Lan T LT Schapiro Denis D Maliga Zoltan Z Jacobson Connor A CA Hendel Ayal A Rozenblatt-Rosen Orit O Mihm Martin C MC Garraway Levi A LA Regev Aviv A

Science (New York, N.Y.) 20220429 6592

Establishing causal relationships between genetic alterations of human cancers and specific phenotypes of malignancy remains a challenge. We sequentially introduced mutations into healthy human melanocytes in up to five genes spanning six commonly disrupted melanoma pathways, forming nine genetically distinct cellular models of melanoma. We connected mutant melanocyte genotypes to malignant cell expression programs in vitro and in vivo, replicative immortality, malignancy, rapid tumor growth, pi ...[more]

PMID: 35482859

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Project description:BackgroundAndrogen deprivation therapy is a first-line treatment for disseminated prostate cancer (PCa). However, virtually all tumors become resistant and recur as castration-resistant PCa, which has no durable cure. One major hurdle in the development of more effective therapies is the lack of preclinical models that adequately recapitulate the heterogeneity of PCa, significantly hindering the ability to accurately predict therapeutic response.ObjectiveTo leverage the ex vivo culture method termed patient-derived explant (PDE) to examine the impact of PCa therapeutics on a patient-by-patient basis.Design setting and participantsFresh PCa tissue from patients who underwent radical prostatectomy was cultured as PDEs to examine therapeutic response.Outcome measurements and statistical analysisThe impact of genomic and chemical perturbations in PDEs was assessed using various parameters (eg, AR levels, Ki67 staining, and desmoplastic indices).Results and limitationsPDE maintained the integrity of the native tumor microenvironment (TME), tumor tissue morphology, viability, and endogenous hormone signaling. Tumor cells in this model system exhibited de novo proliferative capacity. Examination of the native TME in the PDE revealed a first-in-field insight into patient-specific desmoplastic stromal indices and predicted responsiveness to AR-directed therapeutics.ConclusionsThe PDE model allows for a comprehensive evaluation of individual tumors in their native TME to ultimately develop more effective therapeutic regimens tailored to individuals. Discernment of novel stromal markers may provide a basis for applying precision medicine in treating advanced PCa, which would have a transformative effect on patient outcomes.Patient summaryIn this study, an innovative model system was used to more effectively mimic human disease. The patient-derived explant (PDE) system can be used to predict therapeutic response and identify novel targets in advanced disease. Thus, the PDE will be an asset for the development of novel metrics for the implementation of precision medicine in prostate cancer.The patient-derived explant (PDE) model allows for a comprehensive evaluation of individual human tumors in their native tumor microenvironment (TME). TME analysis revealed first-in-field insight into predicted tumor responsiveness to AR-directed therapeutics through evaluation of patient-specific desmoplastic stromal indices.

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Stepwise-edited, human melanoma models reveal mutations' effect on tumor and microenvironment.

Publications

Stepwise-edited, human melanoma models reveal mutations' effect on tumor and microenvironment.

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