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1. Conservation of copy number profiles during engraftment and passaging of patient-derived cancer xenografts

Author

Woo, X.Y., Giordano, J., Srivastava, A., Zhao, Z.-., Lloyd, M.W., de Bruijn, R., Suh, Y.-., Patidar, R., Chen, L., Scherer, S., Bailey, M.H., Yang, C.-., Cortes-Sanchez, E., Xi, Y., Wang, J., Wickramasinghe, J., Kossenkov, A.V., Rebecca, V.W., Sun, H., Mashl, R.J., Davies, S.R., Jeon, R., Frech, C., Randjelovic, J., Rosains, J., Galimi, F., Bertotti, A., Lafferty, A., O'Farrell, A.C., Modave, E., Lambrechts, D., ter Brugge, P., Marangoni, E., El Botty, R., Kim, H., Kim, J.-., Yang, H.-., Lee, C., Dean, D.A., Davis-Dusenbery, B., Evrard, Y.A., Doroshow, J.H., Welm, A.L., Welm, B.E., Lewis, M.T., Fang, B., Roth, J.A., Meric-Bernstam, F., Herlyn, M., Davies, M.A., Ding, L., Li, S., Govindan, R., Isella, C., Moscow, J.A., Trusolino, L., Byrne, A.T., Jonkers, J., Bult, C.J., Medico, E., Chuang, J.H., Robinson, P.N., Sanderson, B.J., Neuhauser, S.B., Dobrolecki, L.E., Zheng, X., Majidi, M., Zhang, R., Zhang, X., Akcakanat, A., Evans, K.W., Yap, T.A., Li, D., Yucan, E., Lanier, C.D., Saridogan, T., Kirby, B.P., M. J., H., Chen, H., Kopetz, S., Menter, D.G., Zhang, J., Westin, S.N., Kim, M.P., Dai, B., Gibbons, D.L., Tapia, C., Jensen, V.B., Boning, G., Minna, J.D., Park, H., Timmons, B.C., Girard, L., Fingerman, D., Liu, Q., Somasundaram, R., Xiao, M., Yennu-Nanda, V.G., Tetzlaff, M.T., Xu, X., Nathanson, K.L., Cao, S., Chen, F., Dipersio, J.F., Lim, K.H., C. X., M., Rodriguez, F.M., Van Tine, B.A., Wang-Gillam, A., Wendl, M.C., Wu, Y., Wyczalkowski, M.A., Yao, L., Jayasinghe, R., Aft, R.L., Fields, R.C., Luo, J., Fuh, K.C., Chin, V., Digiovanna, J., Grover, J., Koc, S., Seepo, S., Wallace, T., Pan, C.-., Chen, M.S., Carvajal-Carmona, L.G., Kirane, A.R., Cho, M., Gandara, D.R., Riess, J.W., Le, T., deVere White, R.W., Tepper, C.G., Zhang, H., Coggins, N.B., Lott, P., Estrada, A., Toal, T., Arana, A.M., Polanco-Echeverry, G., Rocha, S., A. -H., M., Mitsiades, N., Kaochar, S., O'Malley, B.W., Ellis, M.J., Hilsenbeck, S.G., Ittmann, M., Corso, S., Fiori, A., Giordano, S., van de Ven, M., Peeper, D.S., Miller, I., Bernado, C., Morancho, B., Ramirez, L., Arribas, J., Palmer, H.G., Piris-Gimenez, A., Soucek, L., Dahmani, A., Montaudon, E., Nemati, F., Dangles-Marie, V., Decaudin, D., Roman-Roman, S., Alferez, D.G., Spence, K., Clarke, R.B., Bentires-Alj, M., Chang, D.K., Biankin, A.V., Bruna, A., O'Reilly, M., Caldas, C., Casanovas, O., Gonzalez-Suarez, E., Munoz, P., Villanueva, A., Conte, N., Mason, J., Thorne, R., Meehan, T.F., Parkinson, H., Dudova, Z., Krenek, A., Stuchlik, D., Elemento, O., Inghirami, G., Golebiewska, A., Niclou, S.P., Wisman, G.B.A., de Jong, S., Kralova, P., Sedlacek, R., Claeys, E., Leucci, E., Borsani, M., Lanfrancone, L., Pelicci, P.G., Maelandsmo, G.M., Norum, J.H., Vinolo, E., Serra, V., and Leucci, Eleonora

Subjects
endocrine system diseases, Microarray, gene amplification, Whole Exome Sequencing, Mice, 0302 clinical medicine, Gene expression, Databases, Genetic, Gene duplication, Neoplasm Metastasis, Exome sequencing, Cancer, Regulation of gene expression, 0303 health sciences, Manchester Cancer Research Centre, adult, adult, animal experiment, animal model, animal tissue, breast cancer, microarray, DNA sequencing engraftment, gene amplification, tumor, xenograft, tumor-related gene, Polymorphism, Single Nucleotide/genetics, 3. Good health, Gene Expression Regulation, Neoplastic, 030220 oncology & carcinogenesis, microarray, hormones, hormone substitutes, and hormone antagonists, tumor, endocrine system, DNA sequencing engraftment, animal experiment, DNA Copy Number Variations/genetics, Biology, digestive system, DNA sequencing, Article, animal tissue, 03 medical and health sciences, breast cancer, Breast cancer, Genetics, medicine, Animals, Humans, xenograft, Gene, 030304 developmental biology, Settore MED/04 - Patologia Generale, Microarray analysis techniques, animal model, ResearchInstitutes_Networks_Beacons/mcrc, tumor-related gene, medicine.disease, Xenograft Model Antitumor Assays, Computational biology and bioinformatics, Cancer research, Human cancer
Abstract

Patient-derived xenografts (PDXs) are resected human tumors engrafted into mice for preclinical studies and therapeutic testing. It has been proposed that the mouse host affects tumor evolution during PDX engraftment and propagation, affecting the accuracy of PDX modeling of human cancer. Here, we exhaustively analyze copy number alterations (CNAs) in 1,451 PDX and matched patient tumor (PT) samples from 509 PDX models. CNA inferences based on DNA sequencing and microarray data displayed substantially higher resolution and dynamic range than gene expression-based inferences, and they also showed strong CNA conservation from PTs through late-passage PDXs. CNA recurrence analysis of 130 colorectal and breast PT/PDX-early/PDX-late trios confirmed high-resolution CNA retention. We observed no significant enrichment of cancer-related genes in PDX-specific CNAs across models. Moreover, CNA differences between patient and PDX tumors were comparable to variations in multiregion samples within patients. Our study demonstrates the lack of systematic copy number evolution driven by the PDX mouse host., Analysis of copy number alterations in 1,451 patient-derived xenografts (PDXs) and matched patient tumor samples shows strong conservation from patient tumors through late-passage PDXs and a lack of systematic copy number evolution driven by the mouse host.

Published
2021
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3. Diverse clonal fates emerge upon drug treatment of homogeneous cancer cells.

Author

Goyal Y, Busch GT, Pillai M, Li J, Boe RH, Grody EI, Chelvanambi M, Dardani IP, Emert B, Bodkin N, Braun J, Fingerman D, Kaur A, Jain N, Ravindran PT, Mellis IA, Kiani K, Alicea GM, Fane ME, Ahmed SS, Li H, Chen Y, Chai C, Kaster J, Witt RG, Lazcano R, Ingram DR, Johnson SB, Wani K, Dunagin MC, Lazar AJ, Weeraratna AT, Wargo JA, Herlyn M, and Raj A

Subjects
Humans, DNA Barcoding, Taxonomic, RNA-Seq, Single-Cell Gene Expression Analysis, Tumor Cells, Cultured, Clone Cells drug effects, Clone Cells metabolism, Clone Cells pathology, Drug Resistance, Neoplasm drug effects, Drug Resistance, Neoplasm genetics, Neoplasms drug therapy, Neoplasms genetics, Neoplasms pathology, Antineoplastic Agents pharmacology
Abstract

Even among genetically identical cancer cells, resistance to therapy frequently emerges from a small subset of those cells 1-7 . Molecular differences in rare individual cells in the initial population enable certain cells to become resistant to therapy 7-9 ; however, comparatively little is known about the variability in the resistance outcomes. Here we develop and apply FateMap, a framework that combines DNA barcoding with single-cell RNA sequencing, to reveal the fates of hundreds of thousands of clones exposed to anti-cancer therapies. We show that resistant clones emerging from single-cell-derived cancer cells adopt molecularly, morphologically and functionally distinct resistant types. These resistant types are largely predetermined by molecular differences between cells before drug addition and not by extrinsic factors. Changes in the dose and type of drug can switch the resistant type of an initial cell, resulting in the generation and elimination of certain resistant types. Samples from patients show evidence for the existence of these resistant types in a clinical context. We observed diversity in resistant types across several single-cell-derived cancer cell lines and cell types treated with a variety of drugs. The diversity of resistant types as a result of the variability in intrinsic cell states may be a generic feature of responses to external cues., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Published
2023
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4. Dasatinib Resensitizes MAPK Inhibitor Efficacy in Standard-of-Care Relapsed Melanomas.

Author

Rebecca VW, Xiao M, Kossenkov A, Godok T, Brown GS, Fingerman D, Alicea GM, Wei M, Ji H, Bravo J, Chen Y, Fane ME, Villanueva J, Nathanson K, Liu Q, Gopal YNV, Davies MA, and Herlyn M

Abstract

Resistance to combination BRAF/MEK inhibitor (BRAFi/MEKi) therapy arises in nearly every patient with BRAF V600E/K melanoma, despite promising initial responses. Achieving cures in this expanding BRAFi/MEKi-resistant cohort represents one of the greatest challenges to the field; few experience additional durable benefit from immunotherapy and no alternative therapies exist. To better personalize therapy in cancer patients to address therapy relapse, umbrella trials have been initiated whereby genomic sequencing of a panel of potentially actionable targets guide therapy selection for patients; however, the superior efficacy of such approaches remains to be seen. We here test the robustness of the umbrella trial rationale by analyzing relationships between genomic status of a gene and the downstream consequences at the protein level of related pathway, which find poor relationships between mutations, copy number amplification, and protein level. To profile candidate therapeutic strategies that may offer clinical benefit in the context of acquired BRAFi/MEKi resistance, we established a repository of patient-derived xenograft models from heavily pretreated patients with resistance to BRAFi/MEKi and/or immunotherapy (R-PDX). With these R-PDXs, we executed in vivo compound repurposing screens using 11 FDA-approved agents from an NCI-portfolio with pan-RTK, non-RTK and/or PI3K-mTOR specificity. We identify dasatinib as capable of restoring BRAFi/MEKi antitumor efficacy in ~70% of R-PDX tested. A systems-biology analysis indicates elevated baseline protein expression of canonical drivers of therapy resistance (e.g., AXL, YAP, HSP70, phospho-AKT) as predictive of MAPKi/dasatinib sensitivity. We therefore propose that dasatinib-based MAPKi therapy may restore antitumor efficacy in patients that have relapsed to standard-of-care therapy by broadly targeting proteins critical in melanoma therapy escape. Further, we submit that this experimental PDX paradigm could potentially improve preclinical evaluation of therapeutic modalities and augment our ability to identify biomarker-defined patient subsets that may respond to a given clinical trial.

Published
2023
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5. MFF Regulation of Mitochondrial Cell Death Is a Therapeutic Target in Cancer.

Author

Seo JH, Chae YC, Kossenkov AV, Lee YG, Tang HY, Agarwal E, Gabrilovich DI, Languino LR, Speicher DW, Shastrula PK, Storaci AM, Ferrero S, Gaudioso G, Caroli M, Tosi D, Giroda M, Vaira V, Rebecca VW, Herlyn M, Xiao M, Fingerman D, Martorella A, Skordalakes E, and Altieri DC

Subjects
Animals, Apoptosis drug effects, Carcinoma, Non-Small-Cell Lung drug therapy, Cell Line, Tumor, Humans, Lung Neoplasms drug therapy, Male, Membrane Proteins antagonists & inhibitors, Mice, Mitochondria drug effects, Mitochondria metabolism, Mitochondrial Membranes drug effects, Mitochondrial Membranes pathology, Mitochondrial Proteins antagonists & inhibitors, Permeability drug effects, Protein Multimerization drug effects, Voltage-Dependent Anion Channel 1 antagonists & inhibitors, Voltage-Dependent Anion Channel 1 metabolism, Xenograft Model Antitumor Assays, Carcinoma, Non-Small-Cell Lung pathology, Lung Neoplasms pathology, Membrane Proteins metabolism, Mitochondria pathology, Mitochondrial Dynamics drug effects, Mitochondrial Proteins metabolism
Abstract

The regulators of mitochondrial cell death in cancer have remained elusive, hampering the development of new therapies. Here, we showed that protein isoforms of mitochondrial fission factor (MFF1 and MFF2), a molecule that controls mitochondrial size and shape, that is, mitochondrial dynamics, were overexpressed in patients with non-small cell lung cancer and formed homo- and heterodimeric complexes with the voltage-dependent anion channel-1 (VDAC1), a key regulator of mitochondrial outer membrane permeability. MFF inserted into the interior hole of the VDAC1 ring using Arg225, Arg236, and Gln241 as key contact sites. A cell-permeable MFF Ser223-Leu243 d-enantiomeric peptidomimetic disrupted the MFF-VDAC1 complex, acutely depolarized mitochondria, and triggered cell death in heterogeneous tumor types, including drug-resistant melanoma, but had no effect on normal cells. In preclinical models, treatment with the MFF peptidomimetic was well-tolerated and demonstrated anticancer activity in patient-derived xenografts, primary breast and lung adenocarcinoma 3D organoids, and glioblastoma neurospheres. These data identify the MFF-VDAC1 complex as a novel regulator of mitochondrial cell death and an actionable therapeutic target in cancer. SIGNIFICANCE: These findings describe mitochondrial fission regulation using a peptidomimetic agent that disturbs the MFF-VDAC complex and displays anticancer activity in multiple tumor models. See related commentary by Rao, p. 6074 ., (©2019 American Association for Cancer Research.)

Published
2019
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6. Disrupting MLV integrase:BET protein interaction biases integration into quiescent chromatin and delays but does not eliminate tumor activation in a MYC/Runx2 mouse model.

Author

Loyola L, Achuthan V, Gilroy K, Borland G, Kilbey A, Mackay N, Bell M, Hay J, Aiyer S, Fingerman D, Villanueva RA, Cameron E, Kozak CA, Engelman AN, Neil J, and Roth MJ

Subjects
Animals, Chromatin, Core Binding Factor Alpha 1 Subunit genetics, Disease Models, Animal, Genes, myc, Humans, Integrases metabolism, K562 Cells, Leukemia Virus, Murine genetics, Mice, Mice, Transgenic, Virus Integration, Carcinogenesis, Genetic Vectors toxicity, Leukemia, Experimental, Retroviridae Infections, Tumor Virus Infections
Abstract

Murine leukemia virus (MLV) integrase (IN) lacking the C-terminal tail peptide (TP) loses its interaction with the host bromodomain and extraterminal (BET) proteins and displays decreased integration at promoter/enhancers and transcriptional start sites/CpG islands. MLV lacking the IN TP via an altered open reading frame was used to infect tumorigenesis mouse model (MYC/Runx2) animals to observe integration patterns and phenotypic effects, but viral passage resulted in the restoration of the IN TP through small deletions. Mice subsequently infected with an MLV IN lacking the TP coding sequence (TP-) showed an improved median survival by 15 days compared to wild type (WT) MLV infection. Recombination with polytropic endogenous retrovirus (ERV), Pmv20, was identified in seven mice displaying both fast and slow tumorigenesis, highlighting the strong selection within the mouse to maintain the full-length IN protein. Mapping the genomic locations of MLV in tumors from an infected mouse with no observed recombination with ERVs, TP-16, showed fewer integrations at TSS and CpG islands, compared to integrations observed in WT tumors. However, this mouse succumbed to the tumor in relatively rapid fashion (34 days). Analysis of the top copy number integrants in the TP-16 tumor revealed their proximity to known MLV common insertion site genes while maintaining the MLV IN TP- genotype. Furthermore, integration mapping in K562 cells revealed an insertion preference of MLV IN TP- within chromatin profile states associated with weakly transcribed heterochromatin with fewer integrations at histone marks associated with BET proteins (H3K4me1/2/3, and H3K27Ac). While MLV IN TP- showed a decreased overall rate of tumorigenesis compared to WT virus in the MYC/Runx2 model, MLV integration still occurred at regions associated with oncogenic driver genes independently from the influence of BET proteins, either stochastically or through trans-complementation by functional endogenous Gag-Pol protein., Competing Interests: The authors have declared that no competing interests exist.

Published
2019
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