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

描述(申请人提供)：回答这个PQ的一个挑战是天生不能可靠地预测未来。虽然小的非侵袭性病变可以被活检并测量一系列参数，但人们永远不能确定哪些是注定要转移的“进展者”，哪些是终生不会侵袭或转移的“非进展者”。事实上，如果进展到转移是随机的，可能就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的理想工具是时间机器，它允许人们在时间上向前移动，看到病变的命运，然后回到过去，对病变进行活组织检查，并测量进展者和非进展者之间的不同性质。这样的时光机并不存在，但它有可能回到过去，利用现代分子系统学重建过去。我们认为，通过从同一肿瘤的不同部位采样私有(亚克隆)点突变和染色体拷贝数变化，重建当今肿瘤的较小前体是可能的。早期较小的进展性病变可以从转移性肿瘤重建，早期较小的非进展性病变可以从良性肿瘤重建。初步数据表明，肿瘤的转移可能不是随机的，而是从“天生不好”开始的，因为重建的进展性病变与重建的非进展性病变有明显的不同。过去的主要读数是现在肿瘤内的异质性。良性肿瘤有私人的突变斑块，而癌症有私人的突变波尔卡点拓扑图，表明在克隆扩张过程中早期异常的细胞移动或混合分散了突变。异常的细胞流动性是侵袭/转移的先决条件，似乎是一个关键 区分进步者和非进步者的速率限制步骤。小的非侵袭性非进展性病变中的肿瘤细胞具有正常的移动性，并且不混合。相比之下，小的非侵袭性进展性病变中的肿瘤细胞有异常的移动性，并有大量混合的证据。这项拟议的研究旨在重建15个良性肿瘤、10个浸润性癌症和10个转移性癌症的较小祖细胞。结果将证明早期细胞移动性是否能准确区分进展性和非进展性病变。其影响是，对小型非侵入性前体病变中的私人突变拓扑图的测量可能可靠地预测它们的未来。带有私有突变补丁的小病变具有正常的细胞流动性和较低的进展风险(天生就是好的)，但带有私有突变波尔卡点的小病变具有异常的细胞流动性和更高的进展风险(天生就是坏的)。

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).