Scaling concepts in ‘omics: Nuclear lamin-B scales with tumor growth and often predicts poor prognosis, unlike fibrosis

Abstract

Physicochemical principles such as stoichiometry and fractal assembly can give rise to characteristic scaling between components that potentially include coexpressed transcripts. For key structural factors within the nucleus and extracellular matrix, we discover specific gene-gene scaling exponents across many of the 32 tumor types in The Cancer Genome Atlas, and we demonstrate utility in predicting patient survival as well as scaling-informed machine learning (SIML). All tumors with adjacent tissue data show cancer-elevated proliferation genes, with some genes scaling with the nuclear filament LMNB1, including the transcription factor FOXM1 that we show directly regulates LMNB1. SIML shows that such regulated cancers cluster together with longer overall survival than dysregulated cancers, but high LMNB1 and FOXM1 in half of regulated cancers surprisingly predict poor survival, including for liver cancer. COL1A1 is also studied because it too increases in tumors, and a pan-cancer set of fibrosis genes shows substoichiometric scaling with COL1A1 but predicts patient outcome only for liver cancer—unexpectedly being prosurvival. Single-cell RNA-seq data show nontrivial scaling consistent with power laws from bulk RNA and protein analyses, and SIML segregates synthetic from contractile cancer fibroblasts. Our scaling approach thus yields fundamentals-based power laws relatable to survival, gene function, and experiments.

Gaussian curvature dilutes the nuclear lamina, favoring nuclear rupture, especially at high strain rate

“…A- and B-type lamins make ~ 1 / 2 µm-long filaments that resist bending within juxtaposed meshworks at the inner nuclear membrane [ 11 ], and farnesylated lamin-B1 and -B2 associate more directly with the membrane than non-farneslyated lamin-A,C [ 12 , 13 ] ( Figure 1a ). Lamin-B levels are nearly constant across different tissues [ 14 ] and double in level as a cell duplicates its DNA [ 15 ], whereas lamin-A,C increases from low levels in soft embryos and brain to high levels in stiff muscle and rigid bone [ 14 , 16 ]. Various cells studied here are representative with lamin-A:B ratios that range from ~1:1 in early chick embryo hearts [ 16 ] to ~2:1 in A549 human lung cancer cells [ 17 ] and ~7:1 in mesenchymal stem/progenitor cells derived from progeria patient iPS cells [ 18 ].…”

Nuclear mechanoprotection: From tissue atlases as blueprints to distinctive regulation of nuclear lamins

“…Experiments have recently confirmed FOXM1's cell cycle regulation of LMNB1 and, thus, provide a mechanistic basis for a gene-gene scaling relationship between FOXM1 and LMNB1 across many cancers in TCGA ( Vashisth et al , 2021 ). Furthermore, patients with high levels of FOXM1 and LMNB1 have poor survival, consistent with faster cancer growth.…”

“…As with LMNA , the YAP1 gene does not show binding sites for FOXM1 based on the ChIP-seq signal, which again argues against direct cell cycle regulation of YAP1 . In the pan-cancer analysis of TCGA data ( Vashisth et al , 2021 ), tumors had both higher and lower levels of YAP1 relative to adjacent normal tissue, and the variation proved similar to other mechanosensitive genes especially LMNA . Such results concur with the similarities of expression patterns across normal tissues for YAP1 and LMNA [ Figs.…”

“…(b) Regulation of lamin-B1 gene expression based on ChIP-seq targeting FOXM1 in two cultured cell types with nonzero signal from high (black) to low (light gray). (c) Single-cell RNAseq of liver cancer ( Vashisth et al , 2021 ).…”

“…Tissue-level RNA analysis is of course a composite of multiple cell types, but single-cell RNA-seq (scRNAseq) is now becoming publicly accessible for numerous tissues and tumors. We recently analyzed liver cancer data using standard approaches ( Vashisth et al , 2021 ), and the dataset shows more than a half-dozen cell types [ Fig. 2(d) ].…”