All Publications

  • Learning chemical sensitivity reveals mechanisms of cellular response. bioRxiv : the preprint server for biology Connell, W., Garcia, K., Goodarzi, H., Keiser, M. J. 2023


    Chemical probes interrogate disease mechanisms at the molecular level by linking genetic changes to observable traits. However, comprehensive chemical screens in diverse biological models are impractical. To address this challenge, we developed ChemProbe, a model that predicts cellular sensitivity to hundreds of molecular probes and drugs by learning to combine transcriptomes and chemical structures. Using ChemProbe, we inferred the chemical sensitivity of cancer cell lines and tumor samples and analyzed how the model makes predictions. We retrospectively evaluated drug response predictions for precision breast cancer treatment and prospectively validated chemical sensitivity predictions in new cellular models, including a genetically modified cell line. Our model interpretation analysis identified transcriptome features reflecting compound targets and protein network modules, identifying genes that drive ferroptosis. ChemProbe is an interpretable in silico screening tool that allows researchers to measure cellular response to diverse compounds, facilitating research into molecular mechanisms of chemical sensitivity.

    View details for DOI 10.1101/2023.08.26.554851

    View details for PubMedID 37693536

  • A sense-antisense RNA interaction promotes breast cancer metastasis via regulation of NQO1 expression NATURE CANCER Culbertson, B., Garcia, K., Markett, D., Asgharian, H., Chen, L., Fish, L., Navickas, A., Yu, J., Woo, B., Nanda, A., Choi, B., Zhou, S., Rabinowitz, J., Goodarzi, H. 2023: 682-698


    Antisense RNAs are ubiquitous in human cells, yet their role is largely unexplored. Here we profiled antisense RNAs in the MDA-MB-231 breast cancer cell line and its highly lung metastatic derivative. We identified one antisense RNA that drives cancer progression by upregulating the redox enzyme NADPH quinone dehydrogenase 1 (NQO1), and named it NQO1-AS. Knockdown of either NQO1 or NQO1-AS reduced lung colonization in a mouse model, and investigation into the role of NQO1 indicated that it is broadly protective against oxidative damage and ferroptosis. Breast cancer cells in the lung are dependent on this pathway, and this dependence can be exploited therapeutically by inducing ferroptosis while inhibiting NQO1. Together, our findings establish a role for NQO1-AS in the progression of breast cancer by regulating its sense mRNA post-transcriptionally. Because breast cancer predominantly affects females, the disease models used in this study are of female origin and the results are primarily applicable to females.

    View details for DOI 10.1038/s43018-023-00554-7

    View details for Web of Science ID 000986765300002

    View details for PubMedID 37169843

    View details for PubMedCentralID PMC10212767

  • An mRNA processing pathway suppresses metastasis by governing translational control from the nucleus. Nature cell biology Navickas, A., Asgharian, H., Winkler, J., Fish, L., Garcia, K., Markett, D., Dodel, M., Culbertson, B., Miglani, S., Joshi, T., Yin, K., Nguyen, P., Zhang, S., Stevers, N., Hwang, H., Mardakheh, F., Goga, A., Goodarzi, H. 2023


    Cancer cells often co-opt post-transcriptional regulatory mechanisms to achieve pathologic expression of gene networks that drive metastasis. Translational control is a major regulatory hub in oncogenesis; however, its effects on cancer progression remain poorly understood. Here, to address this, we used ribosome profiling to compare genome-wide translation efficiencies of poorly and highly metastatic breast cancer cells and patient-derived xenografts. We developed dedicated regression-based methods to analyse ribosome profiling and alternative polyadenylation data, and identified heterogeneous nuclear ribonucleoprotein C (HNRNPC) as a translational controller of a specific mRNA regulon. We found that HNRNPC is downregulated in highly metastatic cells, which causes HNRNPC-bound mRNAs to undergo 3' untranslated region lengthening and, subsequently, translational repression. We showed that modulating HNRNPC expression impacts the metastatic capacity of breast cancer cells in xenograft mouse models. In addition, the reduced expression of HNRNPC and its regulon is associated with the worse prognosis in breast cancer patient cohorts.

    View details for DOI 10.1038/s41556-023-01141-9

    View details for PubMedID 37156909

  • Small but mighty: microexons in glucose homeostasis. Trends in genetics : TIG Garcia, K., Gloyn, A. L. 2023


    Many molecular mechanisms underlying blood glucose homeostasis remain elusive. Juan-Mateu et al. find that pancreatic islet cells utilize a regulatory program, originally identified in neurons, that involves alternative splicing of microexons in genes important for insulin secretion or diabetes risk.

    View details for DOI 10.1016/j.tig.2023.04.003

    View details for PubMedID 37080883

  • Postmortem Human Dura Mater Cells Exhibit Phenotypic, Transcriptomic and Genetic Abnormalities that Impact their Use for Disease Modeling. Stem cell reviews and reports Argouarch, A. R., Schultz, N., Yang, A. C., Jang, Y., Garcia, K., Cosme, C. G., Corrales, C. I., Nana, A. L., Karydas, A. M., Spina, S., Grinberg, L. T., Miller, B., Wyss-Coray, T., Abyzov, A., Goodarzi, H., Seeley, W. W., Kao, A. W. 2022


    Patient-derived cells hold great promise for precision medicine approaches in human health. Human dermal fibroblasts have been a major source of cells for reprogramming and differentiating into specific cell types for disease modeling. Postmortem human dura mater has been suggested as a primary source of fibroblasts for in vitro modeling of neurodegenerative diseases. Although fibroblast-like cells from human and mouse dura mater have been previously described, their utility for reprogramming and direct differentiation protocols has not been fully established. In this study, cells derived from postmortem dura mater are directly compared to those from dermal biopsies of living subjects. In two instances, we have isolated and compared dermal and dural cell lines from the same subject. Notably, striking differences were observed between cells of dermal and dural origin. Compared to dermal fibroblasts, postmortem dura mater-derived cells demonstrated different morphology, slower growth rates, and a higher rate of karyotype abnormality. Dura mater-derived cells also failed to express fibroblast protein markers. When dermal fibroblasts and dura mater-derived cells from the same subject were compared, they exhibited highly divergent gene expression profiles that suggest dura mater cells originated from a mixed mural lineage. Given their postmortem origin, somatic mutation signatures of dura mater-derived cells were assessed and suggest defective DNA damage repair. This study argues for rigorous karyotyping of postmortem derived cell lines and highlights limitations of postmortem human dura mater-derived cells for modeling normal biology or disease-associated pathobiology.

    View details for DOI 10.1007/s12015-022-10416-x

    View details for PubMedID 35809166

  • A prometastatic splicing program regulated by SNRPA1 interactions with structured RNA elements SCIENCE Fish, L., Khoroshkin, M., Navickas, A., Garcia, K., Culbertson, B., Hanisch, B., Zhang, S., Nguyen, H. B., Soto, L. M., Dermit, M., Mardakheh, F. K., Molina, H., Alarcon, C., Najafabadi, H. S., Goodarzi, H. 2021; 372 (6543): 702-+


    Aberrant alternative splicing is a hallmark of cancer, yet the underlying regulatory programs that control this process remain largely unknown. Here, we report a systematic effort to decipher the RNA structural code that shapes pathological splicing during breast cancer metastasis. We discovered a previously unknown structural splicing enhancer that is enriched near cassette exons with increased inclusion in highly metastatic cells. We show that the spliceosomal protein small nuclear ribonucleoprotein polypeptide A' (SNRPA1) interacts with these enhancers to promote cassette exon inclusion. This interaction enhances metastatic lung colonization and cancer cell invasion, in part through SNRPA1-mediated regulation of PLEC alternative splicing, which can be counteracted by splicing modulating morpholinos. Our findings establish a noncanonical regulatory role for SNRPA1 as a prometastatic splicing enhancer in breast cancer.

    View details for DOI 10.1126/science.abc7531

    View details for Web of Science ID 000651125300039

    View details for PubMedID 33986153

    View details for PubMedCentralID PMC8238114

  • RBMS1 Suppresses Colon Cancer Metastasis through Targeted Stabilization of Its mRNA Regulon CANCER DISCOVERY Yu, J., Navickas, A., Asgharian, H., Culbertson, B., Fish, L., Garcia, K., Olegario, J., Dermit, M., Dodel, M., Hanisch, B., Luo, Y., Weinberg, E. M., Dienstmann, R., Warren, R. S., Mardakheh, F. K., Goodarzi, H. 2020; 10 (9): 1410-1423


    Identifying master regulators that drive pathologic gene expression is a key challenge in precision oncology. Here, we have developed an analytic framework, named PRADA, that identifies oncogenic RNA-binding proteins through the systematic detection of coordinated changes in their target regulons. Application of this approach to data collected from clinical samples, patient-derived xenografts, and cell line models of colon cancer metastasis revealed the RNA-binding protein RBMS1 as a suppressor of colon cancer progression. We observed that silencing RBMS1 results in increased metastatic capacity in xenograft mouse models, and that restoring its expression blunts metastatic liver colonization. We have found that RBMS1 functions as a posttranscriptional regulator of RNA stability by directly binding its target mRNAs. Together, our findings establish a role for RBMS1 as a previously unknown regulator of RNA stability and as a suppressor of colon cancer metastasis with clinical utility for risk stratification of patients. SIGNIFICANCE: By applying a new analytic approach to transcriptomic data from clinical samples and models of colon cancer progression, we have identified RBMS1 as a suppressor of metastasis and as a post-transcriptional regulator of RNA stability. Notably, RBMS1 silencing and downregulation of its targets are negatively associated with patient survival.See related commentary by Carter, p. 1261.This article is highlighted in the In This Issue feature, p. 1241.

    View details for DOI 10.1158/2159-8290.CD-19-1375

    View details for Web of Science ID 000567785900013

    View details for PubMedID 32513775

    View details for PubMedCentralID PMC7483797