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Science Presents Prize Winner for Single-Cell Genomic Methods, Study of Erlotinib Insensitivity in Triple-Negative Breast Cancer

Rockefeller University investigator Junyue Cao is named the winner of Science's Science & SciLifeLab Prize for Young Scientists for his development of a collection of single-cell genomic methods for mapping cell development in whole organisms. The first technique, dubbed sci-RNA-seq — short for single-cell combinatorial indexing RNA sequencing — can be used to process tens of thousands of unsorted cells, and he used it to profile nearly 50,000 Caenorhabditis elegans cells, define consensus expression profiles for 27 cell types, and identify rare neuronal cell types corresponding to as few as one or two cells. The second technique — called sci-RNA-seq3 — allowed him to trace the development of 2 million mouse cells as they traversed diverse paths in a four-day window of development corresponding to organogenesis, then characterize the dynamics of cell proliferation and key regulators for each cell lineage. The third method — single-cell combinatorial indexing chromatin accessibility and mRNA, or sci-CAR — enables the simultaneous profiling of chromatin accessibility and mRNA within single cells. The fourth — sci-fate — identifies the temporal dynamics of transcription by distinguishing newly synthesized mRNA transcripts from older mRNA transcripts in thousands of individual cells.

While activity of the epidermal growth factor receptor (EGFR) pathway is increased in triple-negative breast cancer (TNBC), many patients with this cancer are resistant to EGFR inhibitors such as the chemotherapeutic agent erlotinib. As reported in Science Signaling, investigators from the University of Massachusetts Medical School performed a genome-wide CRISPR-Cas9 genetic knockout screen in TNBC cells and found that these cells produce a prosurvival protein called Mcl-1, which is encoded by the MCL-1 gene. A gene deletion screen revealed that erlotinib insensitivity required MCL-1 expression, which is promoted by the ELP family of transcription-elongation regulators, in particular ELP4. When the scientists inhibited MCL-1 pharmacologically or depleted ELP proteins in TNBC cells, the cells underwent apoptosis in response to erlotinib treatment. "The findings indicate that TNBC 'addiction' to EGFR signaling is masked by the ELP complex and that resistance to EGFR inhibitors in TNBC might be overcome by co-targeting Mcl-1," the authors write.

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