The determination of individual cell trajectories through a high-dimensional cell-state space is an outstanding challenge for understanding biological changes ranging from cellular differentiation to epigenetic responses of diseased cells upon drugging. We integrate experiments and theory to determine the trajectories that single BRAF V600E mutant melanoma cancer cells take between drug-naive and drug-tolerant states. Although single-cell omics tools can yield snapshots of the cell-state landscape, the determination of individual cell trajectories through that space can be confounded by stochastic cell-state switching. We assayed for a panel of signaling, phenotypic, and metabolic regulators at points across 5 days of drug treatment to uncover a cell-state landscape with two paths connecting drug-naive and drugtolerant states. The trajectory a given cell takes depends upon the drug-naive level of a lineage-restricted transcription factor. Each trajectory exhibits unique druggable susceptibilities, thus updating the paradigm of adaptive resistance development in an isogenic cell population.

The mutational activation of oncogenes drives cancer development and progression. Classic oncogenes, such as MYC and RAS, are active across many different cancer types. In contrast, "lineage-survival" oncogenes represent a distinct and emerging class typically comprising transcriptional regulators of a specific cell lineage that, when deregulated, support the proliferation and survival of cancers derived from that lineage. Here, in a large collection of colorectal cancer cell lines and tumors, we identify recurrent amplification of chromosome 13, an alteration highly restricted to colorectal-derived cancers. A minimal region of amplification on 13q12.2 pinpoints caudal type homeobox transcription factor 2 (CDX2), a regulator of normal intestinal lineage development and differentiation, as a target of the amplification. In contrast to its described role as a colorectal tumor suppressor, CDX2 when amplified is required for the proliferation and survival of colorectal cancer cells. Further, transcriptional profiling, binding-site analysis, and functional studies link CDX2 to Wnt/β-catenin signaling, itself a key oncogenic pathway in colorectal cancer. These data characterize CDX2 as a lineage-survival oncogene deregulated in colorectal cancer. Our findings challenge a prevailing view that CDX2 is a tumor suppressor in colorectal cancer and uncover an additional piece in the multistep model of colorectal tumorigenesis.lineage dependency | lineage-addiction oncogene | 13q amplification | CDK8 | integrative genomics

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The tragic murder of Mr. George Floyd brought to the head long-standing issues of racial justice and equity in the United States and beyond. This prompted many institutions of higher education, including professional organizations and societies, to engage in long-overdue conversations about the role of scientific institutions in perpetuating racism. Similar to many professional societies and organizations, the Society for the Advancement of Biology Education Research (SABER), a leading international professional organization for discipline-based biology education researchers, has long struggled with a lack of representation of People of Color (POC) at all levels within the organization. The events surrounding Mr. Floyd’s death prompted the members of SABER to engage in conversations to promote self-reflection and discussion on how the society could become more antiracist and inclusive. These, in turn, resulted in several initiatives that led to concrete actions to support POC, increase their representation, and amplify their voices within SABER. These initiatives included: a self-study of SABER to determine challenges and identify ways to address them, a year-long seminar series focused on issues of social justice and inclusion, a special interest group to provide networking opportunities for POC and to center their voices, and an increase in the diversity of keynote speakers and seminar topics at SABER conferences. In this article, we chronicle the journey of SABER in its efforts to become more inclusive and antiracist. We are interested in increasing POC representation within our community and seek to bring our resources and scholarship to reimagine professional societies as catalyst agents towards an equitable antiracist experience. Specifically, we describe the 12 concrete actions that SABER enacted over a period of a year and the results from these actions so far. In addition, we discuss remaining challenges and future steps to continue to build a more welcoming, inclusive, and equitable space for all biology education researchers, especially our POC members. Ultimately, we hope that the steps undertaken by SABER will enable many more professional societies to embark on their reflection journeys to further broaden scientific communities.