Pan-cancer analyses suggest kindlin-associated global mechanochemical alterations

Area of Science:

• Molecular Biology
• Cancer Research
• Biophysics

Background:

• Kindlins act as mechanosensitive adapters, translating external mechanical forces into internal biochemical signals.
• Dysregulation of kindlins is implicated in cancer development, but their genetic and mechanochemical roles across diverse cancers are not fully understood.

Purpose of the Study:

• To comprehensively analyze genetic alterations in kindlins across various cancer types.
• To investigate the relationship between kindlin alterations, the mechanochemical proteome, and cancer progression.
• To predict the structural and functional impact of cancer-associated kindlin mutations.

Main Methods:

• Analysis of genetic alterations in kindlins across over 10,000 patients with 33 cancer types.
• Co-alteration analysis with the mechanochemical proteome and associated cancer pathways.
• Normal mode analysis to predict structural consequences of kindlin mutations.
• Investigation of epithelial-mesenchymal transition markers related to kindlin activity.

Main Results:

• Identified cancer-specific genetic alterations in kindlins, particularly in advanced stages and during metastasis.
• Revealed significant co-alterations between kindlins and the mechanochemical proteome, linked to activated cancer pathways and poor survival.
• Predicted that specific kindlin mutations impact protein stability and downstream signaling.
• Uncovered alterations in epithelial-mesenchymal transition markers associated with kindlin activity.

Conclusions:

• Kindlin alterations are prevalent in cancer and associated with disease progression and adverse outcomes.
• Kindlins and their mechanochemical interactions represent potential therapeutic targets for cancer treatment.
• This study provides a valuable resource for future research into kindlin-driven cancer mechanisms.