Low lamin A levels enhance confined cell migration and metastatic capacity in breast cancer.
Emily S BellPragya ShahNoam Zuela-SopilniakDongsung KimAlice-Anais VarletJulien L P MorivalAlexandra L McGregorPhilipp IsermannPatricia M DavidsonJoshua J ElacquaJonathan N LakinsLinda VahdatValerie M WeaverMarcus B SmolkaPaul N SpanJan LammerdingPublished in: Oncogene (2022)
Aberrations in nuclear size and shape are commonly used to identify cancerous tissue. However, it remains unclear whether the disturbed nuclear structure directly contributes to the cancer pathology or is merely a consequence of other events occurring during tumorigenesis. Here, we show that highly invasive and proliferative breast cancer cells frequently exhibit Akt-driven lower expression of the nuclear envelope proteins lamin A/C, leading to increased nuclear deformability that permits enhanced cell migration through confined environments that mimic interstitial spaces encountered during metastasis. Importantly, increasing lamin A/C expression in highly invasive breast cancer cells reflected gene expression changes characteristic of human breast tumors with higher LMNA expression, and specifically affected pathways related to cell-ECM interactions, cell metabolism, and PI3K/Akt signaling. Further supporting an important role of lamins in breast cancer metastasis, analysis of lamin levels in human breast tumors revealed a significant association between lower lamin A levels, Akt signaling, and decreased disease-free survival. These findings suggest that downregulation of lamin A/C in breast cancer cells may influence both cellular physical properties and biochemical signaling to promote metastatic progression.
Keyphrases
- cell migration
- breast cancer cells
- signaling pathway
- poor prognosis
- pi k akt
- cell proliferation
- gene expression
- endothelial cells
- single cell
- free survival
- squamous cell carcinoma
- small cell lung cancer
- cell therapy
- binding protein
- mental health
- induced pluripotent stem cells
- stem cells
- physical activity
- long non coding rna
- pluripotent stem cells
- copy number
- cell death
- cell cycle arrest
- childhood cancer
- breast cancer risk
- duchenne muscular dystrophy