Uncovering the basis and implications of lineage plasticity in breast cancer

肿瘤发生涉及遗传异常的积累，导致出现 不同的克隆亚群。跟踪遗传事件进化的研究 而这些克隆种群之间的关系为我们提供了对 肿瘤发生和治疗反应。尽管有这些进展，但转移的过程， 它是癌症相关死亡的90%以上的罪魁祸首，人们对它的了解仍然很少。这个 大多数研究比较了原发肿瘤和转移瘤之间的遗传异常 几乎找不到转移克隆所特有的改变。事实上，目前还没有已知的 复发的转移遗传驱动因素。与原发肿瘤的启动和建立相反， 我自己未来的研究方向假设转移过程不依赖于 在形成原发肿瘤所需的基础上进一步获得新的基因改变 细胞，但取而代之的是染色质景观的变化，以 细胞的可塑性和重新编程的细胞状态。我们发现了流星雨的证据- 腔B分子亚型乳腺癌向基底细胞的转变(LBT)LBT是 对于肿瘤的进展是必不可少的，因为没有表现出这种可塑性的肿瘤表现出减弱 转移能力强，对化疗更敏感。基于这些数据，我们假设 肿瘤细胞可塑性的获得使乳腺癌细胞偏离其 血统是启动转移性级联和疾病的重要第一步。 进步。这种增强的可塑性可能会推动细胞进入一种高度适应 新的栖息地和对与肿瘤微环境成分的相互作用的反应，所有 它们在肿瘤转移过程中起着关键作用。我们建议通过澄清 通过评估细胞的稳定性来评估LBT在B型乳腺癌中的作用 过渡、肿瘤启动能力和转移潜能(目标1)。我们将进一步 通过研究Sox4在全球变暖中的作用，揭示推动这一转变的机制 腔内起源的基底细胞，跟踪其表达并确定其全基因组 占用以揭示其目标基因库在转移进展期间的变化(目标2)。 然后，我们建议测试肿瘤分化的原理作为潜在的佐剂 G-αS R201C/FL联合活化化疗和化疗用药， 或序贯激活GαS R201C/fl，化疗后给药。

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.