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Nahrendorf, Kamila

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Nahrendorf

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Kamila

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Nahrendorf, Kamila
Author's Publications: search.filters.isAuthorOfPublication.f9a97adc-3981-4d05-974b-f86570dff65a

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    Tracing human cancer evolution with hypermutable DNA
    (2014-02-25) Nahrendorf, Kamila; Jain, Rakesh K.; Toker, Alex; Elledge, Stephen; Hynes, Richard; Cepko, Constance
    Metastasis is the main cause of cancer morbidity and mortality. Despite its clinical significance, several fundamental questions about the metastatic process in humans remain unsolved. Does metastasis occur early or late in cancer progression? Do metastases emanate directly from the primary tumor or give rise to each other? How does heterogeneity in the primary tumor relate to the genetic composition of secondary lesions? Addressing these questions in representative patient populations is crucial, but has been difficult so far. Here we present a simple, scalable PCR assay that enables the tracing of tumor lineage in patient tissue specimens. Our methodology relies on somatic variation in highly mutable polyguanine (poly-G) repeats located in non-coding genomic regions. We show that poly-G mutations are present in a variety of human cancers. Using colon carcinoma as an example, we demonstrate an association between patient age at diagnosis and tumor mutational burden, suggesting that poly-G variants accumulate during normal division in colonic stem cells. We further show that poorly differentiated colon carcinomas have fewer mutations than well-differentiated tumors, possibly indicating a shorter mitotic history of the founder cell in these cancers. We collect multiple spatially separated samples from primary carcinomas and their metastases and use poly-G fingerprints to build well-supported phylogenetic trees that illuminate each patient's path of progression. Our results imply that levels of intra-tumor heterogeneity vary significantly among patients.
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    Origins of lymphatic and distant metastases in human colorectal cancer
    (American Association for the Advancement of Science (AAAS), 2017) Nahrendorf, Kamila; Reiter, Johannes; Brachtel, Elena; Lennerz, Jochen; van de Wetering, Marc; Rowan, Andrew; Cai, Tianxi; Clevers, Hans; Swanton, Charles; Nowak, Martin; Elledge, Stephen; Jain, Rakesh
    The spread of cancer cells from primary tumors to regional lymph nodes is often associated with reduced survival. One prevailing model to explain this association posits that fatal, distant metastases are seeded by lymph node metastases. This view provides a mechanistic basis for the TNM staging system and is the rationale for surgical resection of tumor-draining lymph nodes. Here we examine the evolutionary relationship between primary tumor, lymph node, and distant metastases in human colorectal cancer. Studying 213 archival biopsy samples from 17 patients, we used somatic variants in hypermutable DNA regions to reconstruct high-confidence phylogenetic trees. We found that in 65% of cases, lymphatic and distant metastases arose from independent subclones in the primary tumor, whereas in 35% of cases they shared common subclonal origin. Therefore, two different lineage relationships between lymphatic and distant metastases exist in colorectal cancer.
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    Myocardial Infarction Activates CCR2+ Hematopoietic Stem and Progenitor Cells
    (Elsevier BV, 2015) Dutta, Partha; Sager, Hendrik B; Stengel, Kristy R.; Nahrendorf, Kamila; Courties, Gabriel; Saez, Borja; Silberstein, Lev; Heidt, Timo; Sebas, Matthew; Sun, Yuan; Wojtkiewicz, Gregory; Feruglio, Paolo Fumene; King, Kevin Robert; Baker, Joshua N.; van der Laan, Anja M.; Borodovsky, Anna; Fitzgerald, Kevin; Hulsmans, Maarten; Hoyer, Friedrich; Iwamoto, Yoshiko; Vinegoni, Claudio; Brown, Dennis; Di Carli, Marcelo; Libby, Peter; Hiebert, Scott W.; Scadden, David; Swirski, Filip; Weissleder, Ralph; Nahrendorf, Matthias
    Following myocardial infarction (MI), myeloid cells derived from the hematopoietic system drive a sharp increase in systemic leukocyte levels that correlates closely with mortality. The origin of these myeloid cells, and the response of hematopoietic stem and progenitor cells (HSPCs) to MI, however, is unclear. Here, we identify a CCR2+CD150+CD48− LSK hematopoietic subset as the most upstream contributor to emergency myelopoiesis after ischemic organ injury. This subset has 4-fold higher proliferation rates than CCR2−CD150+CD48− LSK cells, displays a myeloid differentiation bias, and dominates the migratory HSPC population. We further demonstrate that the myeloid translocation gene 16 (Mtg16) regulates CCR2+ HSPC emergence. Mtg16−/− mice have decreased levels of systemic monocytes and infarct-associated macrophages and display compromised tissue healing and post-MI heart failure. Together, these data provide insights into regulation of emergency hematopoiesis after ischemic injury and identify potential therapeutic targets to modulate leukocyte output after MI.
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    Analysis of Gene Expression in a Developmental Context Emphasizes Distinct Biological Leitmotifs in Human Cancers
    (BioMed Central, 2008) Nahrendorf, Kamila; Bult, Carol J; Peaston, Anne; Fancher, Karen; Knowles, Barbara B; Kasif, Simon; Kohane, Isaac
    A systematic analysis of the relationship between the neoplastic and developmental transcriptome provides an outline of global trends in cancer gene expression.