Scaling concepts in ’omics: nuclear lamin-B scales with tumor growth and predicts poor prognosis, whereas fibrosis can be pro-survival

Abstract

Spatiotemporal relationships between genes expressed in tissues likely reflect physicochemical principles that range from stoichiometric interactions to co-organized fractals with characteristic scaling. For key structural factors within the nucleus and extracellular matrix (ECM), gene-gene power laws are found to be characteristic across several tumor types in The Cancer Genome Atlas (TCGA) and across single-cell RNA-seq data. The nuclear filament LMNB1 scales with many tumor-elevated proliferation genes that predict poor survival in liver cancer, and cell line experiments show LMNB1 regulates cancer cell cycle. Also high in the liver, lung, and breast tumors studied here are the main fibrosis-associated collagens, COL1A1 and COL1A2, that scale stoichiometrically with each other and superstoichiometrically with a pan-cancer fibrosis gene set. However, high fibrosis predicts prolonged survival of patients undergoing therapy and does not correlate with LMNB1. Single-cell RNA-seq data also reveal scaling consistent with the pan-cancer power laws obtained from bulk tissue, allowing new power law relations to be predicted. Lastly, although noisy data frustrate weak scaling, concepts such as stoichiometric scaling highlight a simple, internal consistency check to qualify expression data.

Pan-tissue scaling of stiffness versus fibrillar collagen reflects contractility-driven strain that inhibits fibril degradation

“…Robust scaling can help clarify the accuracy of measurements as well as the effects of tissue treatments (e.g. drugs) and diseases such as fibrosis and cancer [3]. Pan-tissue studies with methods such as single-cell RNAsequencing enable novel comparisons [4], but for the most abundant animal protein, trends and underlying mechanisms remain obscure.…”

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

“…A- and B-type lamins make ~½-μm long filaments that resist bending within juxtaposed meshworks at the inner nuclear membrane (Turgay et al, 2017), and farnesylated lamin-B1 and -B2 associate more directly with the membrane than non-farneslyated lamin-A,C ( Fig.1A ). Lamin-B levels are nearly constant across different tissues (Swift et al, 2013) and double in level as a cell duplicates its DNA (Vashisth et al, 2021), whereas lamin-A,C increases from low levels in soft embryos and brain to high levels in stiff muscle and rigid bone (Cho et al, 2019; Swift et al, 2013). Various cells studied here are representative with lamin-A:B ratios that range from ~1:1 in early chick embryo hearts (Cho et al, 2019) to ~2:1 in A549 human lung cancer cells (Harada et al, 2014) and ~7:1 in mesenchymal stem/progenitors derived from progeria patient iPS cells (Cho et al, 2018) – all of which provide broad insight into how the lamins confer nuclear strength and stability.…”