Evolution of placental invasion and cancer metastasis are causally linked

Kshitiz, .; Afzal, Junaid; Maziarz, Jamie; Hamidzadeh, Archer; Liang, Cong; Erkenbrack, Eric M.; Kim, Hong Nam; Haeger, J.-D.; Pfarrer, Christiane; Hoang, Thomas; Ott, Troy L.; Spencer, Thomas E.; Pavličev, Mihaela; Antczak, Douglas F.; Levchenko, Andre; Wagner, Günter P.

doi:10.1038/s41559-019-1046-4

Cited by 61 publications

(79 citation statements)

References 75 publications

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“…The ELI hypothesis states that bovine stromal fibroblasts, both in endometrium and skin, have evolved to be more resistant to trophoblast and cancer cell invasion than their human counterparts 13 ( Figure 1A ). To explore the evolutionary history of genes that have changed along with non-invasive epitheliochorial placentation, we expanded the number of eutherian species in our transcriptomic analysis.…”

Section: Resultsmentioning

confidence: 99%

“…The colors correspond to the effect size, with blue for an overall increase of gene expression with the particular TF binding in its promoter region, and orange for an overall decreasing effect for additional binding. (G) Transcription factor binding sites whose occurrence is related to the expression of genes experimentally tested 13 for their role in modulating invasibility. Each point represents a binding site sequence motif, with the mean variance explained on the y-axis and the number of genes with p-value < .05 for the correlation on the x-axis.…”

Section: Resultsmentioning

confidence: 99%

“…Genomically informed phylogeny construction showed that the epitheliochorial placentation has evolved more recently from the ancestral hemochorial placentation, which is present in the stem lineage of eutherian mammals 6 . We have hypothesized, and experimentally validated that the evolution of epitheliochorial placentation is in part a stromal characteristic, which has resulted in the stromal fibroblasts to attain increased resistance to invasion from placental trophoblasts 13 . This hypothesis, termed the Evolved Levels of Invasibility (ELI) posits that stromal invasibility itself is an evolved phenotype, resulting in higher resistance to trophoblast invasion within bovines (and other species with epitheliochorial placentation).…”

Section: Introductionmentioning

confidence: 99%

“…This hypothesis, termed the Evolved Levels of Invasibility (ELI) posits that stromal invasibility itself is an evolved phenotype, resulting in higher resistance to trophoblast invasion within bovines (and other species with epitheliochorial placentation). Notably, its secondary manifestation in other stromal tissues also limit cancer dissemination, suggesting a heritable, genomic basis for the establishment of the phenotype 13,14 . In this paper, we explore the extent to which genomic changes explain the variation in stromal invasibility in a larger cohort of mammalian species.…”

Section: Introductionmentioning

confidence: 99%

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Cis-Regulatory Differences Explaining Evolved Levels of Endometrial Invasibility in Eutherian Mammals

Suhail

Maziarz

Dighe

et al. 2020

Preprint

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Eutherian (placental) mammals exhibit great differences in the degree of placental invasion into the maternal endometrium, with humans being on the most invasive end. Previously, we have shown that these differences in invasiveness is largely controlled by the stromal fibroblasts of the maternal endometrium, with secondary effect on stroma of other tissues resulting in correlated differences in cancer malignancy. Here, we present a statistical investigation of the second dogma linking the phenotypic and transcriptional differences to the genomic changes across species, revealing the regulatory genomic sequence differences underlying these inter-species differences. We show that gain or loss of specific transcription factor binding site sequences are connected to the inter-species gene-expression differences in a statistically significant manner, with a particularly larger effect on stromal genes related to invasibility. We also uncover transcriptional factors differentially regulating genes related to pro- and anti- invasible property of stroma. This work extends the understanding of inter-species differences in stromal invasion to the causal genomic sequence differences paving new avenues to target stromal characteristics to regulate placental, or cancer invasion.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Cis-Regulatory Differences Explaining Evolved Levels of Endometrial Invasibility in Eutherian Mammals

Suhail

Maziarz

Dighe

et al. 2020

Preprint

Self Cite

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“…Cancer could be cost to becoming a placental animal. Placentation and embryo implantation share similar biological processes to malignancy, including growth, invasion, and vascularization ( D'Souza and Wagner, 2014 ; Haig, 2015 ; Kshitiz et al., 2019 ). These observations suggest mammals may be more susceptible to tissue-specific malignancy, such as tumors originating from epithelial origins; however, better comparative pathology data are needed to test this.…”

Section: Summary Of Current Comparative Oncology Datamentioning

confidence: 99%

Comparative Oncology: New Insights into an Ancient Disease

2020

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Summary Cancer has deep evolutionary roots and is an important source of selective pressure in organismal evolution. Yet, we find a great deal of variation in cancer vulnerabilities across the tree of life. Comparative oncology offers insights into why some species vary in their susceptibility to cancer and the mechanisms responsible for the diversity of cancer defenses. Here we provide an overview for why cancer persists across the tree of life. We then summarize current data on cancer in mammals, reptiles, and birds in comparison with commonly reported human cancers. We report on both novel and shared mechanisms of cancer protection in animals. Cross-discipline collaborations, including zoological and aquarium institutions, wildlife and evolutionary biologists, veterinarians, medical doctors, cancer biologists, and oncologists, will be essential for progress in the field of comparative oncology. Improving medical treatment of humans and animals with cancer is the ultimate promise of comparative oncology.

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Tissue‐of‐origin for cancers determines HIF‐1 activation induced phenotypic heterogeneity

Liu,

Qiu

et al. 2024

Molecular Carcinogenesis

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Hypoxia‐inducible factor‐1 (HIF‐1) is the master regulator of cellular response to hypoxia, and is activated in many cancers contributing to many steps in the metastatic cascade by acting as a key transcription co‐regulator for a large number of downstream genes. Presence of hypoxia within a tumor is spatially nonuniform, and can also by dynamic. Further, although HIF‐1 is primarily stabilized and activated by lack of molecular O2, its stability is also affected by other factors present in the tumor microenvironment. HIF‐1 also crosstalks with other transcription factors in co‐regulating gene expression. Consequently, it is nontrivial to predict the gene expression patterns in cells in response to hypoxia, or HIF‐1 activation. Additionally, cancers originating from tissue origins with different basal level of partial oxygen tension may activate HIF‐1 at different threshold of hypoxia. We analyzed large published single cell RNAseq data for colorectal, lung, and pancreatic cancers to investigate the phenotypic outcome of HIF‐1 activation in cancer cells. We found that cancers from tissues with different partial O2 tension levels exhibit HIF‐1 activation at different stages of metastasis, and phenotypically respond differently to HIF‐1 activation, likely by contextual co‐option of different transcription factors. We experimentally confirmed these predictions by using cell lines representative of colorectal, lung, and pancreatic cancers, finding that while hypoxia enhances growth of colorectal cancer, it induces increased invasion of lung, and pancreatic cancers. Our analysis suggest that HIF‐1 activation may act as a rheostat regulating downstream gene expression towards phenotypic outcomes differently in various cancers.

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Evolution of placental invasion and cancer metastasis are causally linked

Cited by 61 publications

References 75 publications

Cis-Regulatory Differences Explaining Evolved Levels of Endometrial Invasibility in Eutherian Mammals

Cis-Regulatory Differences Explaining Evolved Levels of Endometrial Invasibility in Eutherian Mammals

Comparative Oncology: New Insights into an Ancient Disease

Tissue‐of‐origin for cancers determines HIF‐1 activation induced phenotypic heterogeneity

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