Tracing human cancer evolution with hypermutable DNA

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

Analysis of Gene Expression in a Developmental Context Emphasizes Distinct Biological Leitmotifs in Human Cancers

A systematic analysis of the relationship between the neoplastic and developmental transcriptome provides an outline of global trends in cancer gene expression

The brain microenvironment mediates resistance in luminal breast cancer to PI3K inhibition through HER3 activation

Although targeted therapies are often effective systemically, they fail to adequately control brain metastases. In preclinical models of breast cancer that faithfully recapitulate the disparate clinical responses in these microenvironments, we observed that brain metastases evade phosphatidylinositide 3-kinase (PI3K) inhibition despite drug accumulation in the brain lesions. In comparison to extracranial disease, we observed increased HER3 expression and phosphorylation in brain lesions. HER3 blockade overcame the resistance of HER2-amplified and/or PIK3CA-mutant breast cancer brain metastases to PI3K inhibitors, resulting in marked tumor growth delay and improvement in mouse survival. These data provide a mechanistic basis for therapeutic resistance in the brain microenvironment and identify translatable treatment strategies for HER2-amplified and/or PIK3CA-mutant breast cancer brain metastases

Lymphatic Invasion of Plakoglobin-Dependent Tumor Cell Clusters Drives Formation of Polyclonal Lung Metastases in Colon Cancer

Background & Aims: Patients with colon cancer with liver metastases may be cured with surgery, but the presence of additional lung metastases often precludes curative treatment. Little is known about the processes driving lung metastasis. This study aimed to elucidate the mechanisms governing lung vs liver metastasis formation. Methods: Patient-derived organoid (PDO) cultures were established from colon tumors with distinct patterns of metastasis. Mouse models recapitulating metastatic organotropism were created by implanting PDOs into the cecum wall. Optical barcoding was applied to trace the origin and clonal composition of liver and lung metastases. RNA sequencing and immunohistochemistry were used to identify candidate determinants of metastatic organotropism. Genetic, pharmacologic, in vitro, and in vivo modeling strategies identified essential steps in lung metastasis formation. Validation was performed by analyzing patient-derived tissues. Results: Cecum transplantation of 3 distinct PDOs yielded models with distinct metastatic organotropism: liver only, lung only, and liver and lung. Liver metastases were seeded by single cells derived from select clones. Lung metastases were seeded by polyclonal clusters of tumor cells entering the lymphatic vasculature with very limited clonal selection. Lung-specific metastasis was associated with high expression of desmosome markers, including plakoglobin. Plakoglobin deletion abrogated tumor cell cluster formation, lymphatic invasion, and lung metastasis formation. Pharmacologic inhibition of lymphangiogenesis attenuated lung metastasis formation. Primary human colon, rectum, esophagus, and stomach tumors with lung metastases had a higher N-stage and more plakoglobin-expressing intra-lymphatic tumor cell clusters than those without lung metastases. Conclusions: Lung and liver metastasis formation are fundamentally distinct processes with different evolutionary bottlenecks, seeding entities, and anatomic routing. Polyclonal lung metastases originate from plakoglobin-dependent tumor cell clusters entering the lymphatic vasculature at the primary tumor site

Taking the brakes off telomerase

Studies using human embryonic stem cells have revealed how common cancer-associated mutations exert their effect on telomerase after cells differentiate into more specialized cell types

Should we talk about the ‘benefits’ of breastfeeding? The significance of the default in representations of infant feeding

Breastfeeding advocates have criticized the phrase “breast is best” as mistakenly representing breastfeeding as a departure from the norm rather than the default for infant feeding. Breastfeeding mothers have an interest in representing breastfeeding as the default, for example to counteract criticism of breastfeeding outside the home. This connects to an increasing trend to frame feeding babies formula as harmful which can be seen in research papers, public policy and information presented to parents and prospective parents. (1) whether we frame infant feeding decisions in terms of harming or benefit, protection or risk matters because these distinctions are generally morally significant and thus (2) holding that those who decide to use formula “harm”, “risk harm” to their babies or describing formula feeding as “dangerous” is likely to contribute to guilt associated with formula feeding and thus to undermine the wellbeing of vulnerable women. It may undermine attempts to improve breastfeeding rates by leading women to reject information about health outcomes surrounding infant feeding decisions. However, (3) these distinctions do not apply easily to infant feeding decisions, in part because of difficulties in determining whether we should treat breastfeeding as the normative baseline for infant feeding. I show that neither the descriptive ‘facts of the matter’ nor moral or pragmatic considerations provide an easy answer before discussing how to respond to these considerations. Keywords: Breastfeeding, Harm, Benefit, Risk-Based Language<br/

Heatmap of probability distribution slopes for all data sets with respect to the lung development validation time series

Abbreviations and colors are the same as in Figure 3.<p><b>Copyright information:</b></p><p>Taken from "Analysis of gene expression in a developmental context emphasizes distinct biological leitmotifs in human cancers"</p><p>http://genomebiology.com/2008/9/7/R108</p><p>Genome Biology 2008;9(7):R108-R108.</p><p>Published online 8 Jul 2008</p><p>PMCID:PMC2530866.</p><p></p

Average expression level of consensus gene sets in the lung development validation time series

Consensus group 1 = genes overexpressed in 11/16 data sets belonging to group 1; consensus group 2 = genes overexpressed in 5/6 data sets belonging to group 2; consensus group 3 = genes overexpressed in 8/13 data sets belonging to group 3.<p><b>Copyright information:</b></p><p>Taken from "Analysis of gene expression in a developmental context emphasizes distinct biological leitmotifs in human cancers"</p><p>http://genomebiology.com/2008/9/7/R108</p><p>Genome Biology 2008;9(7):R108-R108.</p><p>Published online 8 Jul 2008</p><p>PMCID:PMC2530866.</p><p></p