Uncovering the basis and implications of lineage plasticity in breast cancer

肿瘤发生涉及遗传畸变的积累，导致肿瘤的出现。 不同的克隆亚群。研究追踪了人类基因组中的遗传事件的进化， 以及这些克隆种群之间的关系，为我们深入了解 肿瘤发生和对治疗的反应。尽管有这些进展，转移的过程， 导致超过90%的癌症相关死亡的原因仍然知之甚少。的 大多数比较原发肿瘤和转移瘤之间遗传畸变的研究 发现转移性克隆所特有的一些改变。的确，没有人知道。 复发性转移的遗传驱动因素。与原发性肿瘤的起始和建立相反， 我自己未来的研究方向假设转移的过程并不依赖于 在形成原发性肿瘤所需的基因改变之外进一步获得新的基因改变 细胞，而是由染色质景观的改变驱动，以形式呈现 细胞可塑性和重新编程的细胞状态。我们发现了一种管腔- 管腔型B分子亚型乳腺癌中的基底转移（LBT）。LBT是 对于肿瘤进展至关重要，因为不表现出这种可塑性的肿瘤表现出减弱的 转移能力，对化疗更敏感。根据这些数据，我们假设 获得肿瘤细胞的可塑性，使乳腺癌细胞偏离其 起源谱系是启动转移级联反应和疾病的重要第一步 进展这种增加的可塑性可能会促使细胞进入一种高度适应的状态， 新的栖息地和响应与肿瘤微环境的成分的相互作用，所有 这些基因对转移过程至关重要。我们建议通过阐明 LBT在管腔型B乳腺癌中的作用，通过评估经历LBT的细胞的稳定性， 转变、其肿瘤引发能力和转移潜力（目标1）。我们将进一步 通过研究Sox 4在出现中的作用，揭示推动这种转变的机制。 腔起源的基底细胞，跟踪其表达并确定其全基因组 占位以揭示转移进展期间其靶基因库的变化（aim 2）。 然后，我们建议测试肿瘤分化的原则，作为一个潜在的佐剂， 通过Gαs R201 C/fl的组合活化和化疗施用进行化疗， 或通过Gαs R201 C/fl的顺序激活，随后化疗给药。

Tumorigenesis involves the accumulation of genetic aberrations, leading to the emergence of distinct clonal subpopulations. Studies that have tracked the evolution of genetic events within and between these clonal populations have provided deep insights into the process of tumorigenesis and response to therapy. Despite these advances, the process of metastasis, which is responsible for over 90% of cancer-related deaths, remains poorly understood. The majority of studies that compare genetic aberrations between the primary tumor and metastases find few alterations that are unique to the metastatic clone. Indeed, there are no known recurrent genetic drivers of metastasis. In contrast to primary tumor initiation and establishment, my own future research directions hypothesize that the process of metastasis does not rely on the further acquisition of novel genetic alterations beyond those needed to form primary tumor cells, but is instead driven by alterations to the chromatin landscape, presenting itself in the form of cellular plasticity and a reprogrammed cell state. We have uncovered evidence of a luminal- to-basal transition (LBT) in breast cancers of the luminal B molecular subtype. The LBT is essential for tumor progression as tumors that do not exhibit this plasticity show attenuated metastatic ability and are more sensitive to chemotherapy. Based on these data we hypothesize that the acquisition of tumor cell plasticity that allows breast cancer cells to stray from their lineage-of-origin is an essential first step to initiating the metastatic cascade and disease progression. This increased plasticity likely propels cells into a state that is highly adaptive to new habitats and responsive to interactions with components of the tumor microenvironment, all of which are critical to the process of metastasis. We propose to test this by elucidating the effects of the LBT in luminal B breast cancers by assessing the stability of the cells that undergo the transition, their tumor-initiating capacity and metastatic potential (aim 1). We will further uncover the mechanisms driving the transition by studying the role of Sox4 in the emergence of the basal cells of luminal origin, tracking its expression and determining its genome-wide occupancy to reveal changes to its target gene repertoire during metastatic progression (aim 2). We then propose to test the principle of tumor differentiation as a potential adjuvant to chemotherapy by either combinatorial activation of Gαs R201C/fl and chemotherapy administration, or by sequential activation of Gαs R201C/fl followed by chemotherapy administration.