"Born to be Bad": Is Abnormal Cell Mobility Already Present At Initiation?

描述（由申请人提供）：回答这个PQ的一个挑战是固有的无法可靠地预测未来。虽然小的、非侵入性的病变可以通过活检和测量一系列参数，但人们永远无法确定哪些是注定要转移的“进展者”，哪些是在一生中不会侵入或转移的“非进展者”。事实上，如果进展到转移是随机的，可能没有办法区分进展性和非进展性病变，因为任何细胞都可以随机转移。回答这个PQ的一个理想工具是时光机，它允许一个人在时间上向前移动，看到病变的命运，然后回到过去，对病变进行活检，并测量进展者和非进展者之间的不同特性。这样的时间机器并不存在，但利用现代分子系统发育，回到过去重建过去是可能的。我们提出，这是可能的重建一个较小的祖目前的肿瘤通过采样私人（亚克隆）点突变和染色体拷贝数改变从同一肿瘤的不同部分。早期较小的进展性病变可由转移性肿瘤重建，早期较小的非进展性病变可由良性肿瘤重建。初步数据表明，转移可能不是随机的，而是肿瘤一开始就“生来就是坏的”，因为重建的进展性病变与重建的非进展性病变明显不同。过去的主要解读是当今肿瘤的肿瘤内异质性。良性肿瘤有单独的突变斑块，而癌症有单独的突变波尔卡点地形，表明在克隆扩增过程中早期异常的细胞迁移或分散突变的混合。异常的细胞移动是侵袭/转移的先决条件，似乎是一个关键因素

DESCRIPTION (provided by applicant): A challenge to answering this PQ is the inherent inability to reliably predict the future. Although small, non-invasive lesions can be biopsied and measured for a host of parameters, one can never be sure which ones are "progressors" destined to metastasize and which ones are "nonprogressors" that will not invade or metastasize within a lifetime. Indeed, if progression to metastasis is stochastic, there may be no way to distinguish between progressors and nonprogressor lesions because any cell can randomly become metastatic. An ideal tool to answer this PQ is a time machine, allowing one to move forward in time to see the fate of a lesion, and then back in time to biopsy the lesion and measure properties that differ between progressors and nonprogressors. Such a time machine does not exist, but it is possible to go back in time to reconstruct the past using modern molecular phylogeny. We propose that it is possible to reconstruct the smaller progenitor of a present day tumor by sampling private (subclonal) point mutations and chromosome copy number alterations from different parts of the same tumor. Earlier smaller progressor lesions can be reconstructed from metastatic tumors, and earlier smaller nonprogressor lesions can be reconstructed from benign tumors. Preliminary Data indicate that metastasis may not be stochastic but rather that tumors start out "Born to Be Bad" because reconstructed progressor lesions are measurably different from reconstructed nonprogressor lesions. The primary readout of the past is the intratumoral heterogeneity in the present day tumor. Benign tumors have private mutation patches whereas cancers have private mutation polka dot topographies that indicate early abnormal cell mobility or intermixing that scatters mutations during clonal expansion. Abnormal cell mobility, a prerequisite for invasion/metastasis, appears to be a critical rate limiting step that distinguishes progressors from nonprogressors. Tumor cells in small non-invasive nonprogressor lesions have normal mobility and do not intermix. By contrast, tumor cells in small non-invasive progressor lesions have abnormal mobility, with evidence of substantial intermixing. The proposed studies are designed to reconstruct the smaller progenitors of 15 benign tumors, 10 invasive cancers, and 10 metastatic cancers. The results will demonstrate whether early cell mobility accurately distinguishes progressors from nonprogressor lesions. The impact is that measurements of private mutation topographies in small non-invasive progenitor lesions may reliably foretell their futures. A small lesion with private mutation patches has normal cell mobility and a low risk of progression (Born to Be Good), but a small lesion with private mutation polka dots has abnormal cell mobility and a higher risk of progression (Born to Be Bad).