Decision letter for "Dorsoventral inversion of the air‐filled organ (lungs, gas bladder) in vertebrates: RNAsequencing of laser capture microdissected embryonic tissue"

ABSTRACTStarting from the zygote, all cells in the developing and adult human body continuously acquire mutations. A mutation shared between two different cells implies a shared progenitor cell and can thus be used as a naturally occurring marker for lineage tracing. Here, we reconstruct extensive phylogenies of normal tissues from three adult individuals using whole-genome sequencing of 511 laser capture microdissected samples from multiple organs. Early embryonic progenitor cells inferred from the phylogenies often contribute in different proportions to the adult body and the extent of this asymmetry is variable between individuals, with ratios between the first two reconstructed cells ranging from 56:44 to 92:8. Asymmetries also pervade subsequent cell generations and can differ between tissues in the same individual. The phylogenies also resolve the spatial embryonic origins and patterning of tissues, revealing a spatial effect in the development of the human brain. Supplemented by data on eleven men, we timed the split between soma and germline, with the earliest observed segregation occurring at the first cell divisions. This research demonstrates that, despite reaching the same ultimate tissue patterns, early bottlenecks and lineage commitments lead to substantial variation in embryonic patterns both within and between individuals.

Download Full-text

Differential stromal reprogramming in benign and malignant naturally occurring canine mammary tumours identifies disease-promoting stromal components

10.1101/783621 ◽

2019 ◽

Author(s):

Parisa Amini ◽

Sina Nassiri ◽

Alexandra Malbon ◽

Enni Markkanen

Keyword(s):

Screening Method ◽

Malignant Tumours ◽

Differential Abundance ◽

Naturally Occurring ◽

Mammary Tumours ◽

Ffpe Specimen ◽

Summary Statement ◽

Benign Tumours ◽

Laser Capture ◽

Laser Capture Microdissected

AbstractThe importance of cancer-associated stroma (CAS) for initiation and progression of cancer is well accepted. However, as stromal changes in benign forms of naturally occurring tumours are poorly understood, it remains unclear how CAS from benign and malignant tumours compare. Spontaneous canine mammary tumours are viewed as excellent models of human mammary carcinomas (mCA). We have recently reported highly conserved stromal reprogramming between canine and human mCA based on transcriptome analysis of laser-capture-microdissected FFPE specimen. To identify stromal changes between benign and malignant mammary tumours, we have analysed CAS and matched normal stroma from 13 canine mammary adenomas and compared them to 15 canine mCA. Our analyses revealed distinct stromal reprogramming even in small benign tumours. While similarities in stromal reprogramming exist, the CAS signature clearly distinguished adenomas from mCA, suggesting that it may reliably discriminate between benign and malignant tumours. We identified strongly discriminatory genes and found strong differential enrichment in several hallmark signalling pathways between benign and malignant CAS. The distinction between CAS from adenoma and mCA was further substantiated by differential abundance in cellular composition. Finally, to determine key players in CAS reprograming between adenomas and mCA, a network-based gene screening method identified modules of co-expressing genes with distinct expression profile in benign and malignant CAS, and revealed several hub genes as potential molecular drivers in CAS. Given the relevance of canine CAS as a model for the human disease, our approach identifies potential stromal drivers of tumour malignancy with implications for human mCA.Summary statementRNAsequencing-based analysis of stromal reprogramming between benign and malignant naturally occurring canine mammary tumours identifies potential molecular drivers in cancer-associated stroma that support tumour growth and malignancy.

Download Full-text