Low lamin A levels enhance confined cell migration and metastatic capacity in breast cancer

Emily S. Bell, Pragya Shah, Noam Zuela-Sopilniak, Dongsung Kim, Alice Anais Varlet, Julien L.P. Morival, Alexandra L. McGregor, Philipp Isermann, Patricia M. Davidson, Joshua J. Elacqua, Jonathan N. Lakins, Linda Vahdat, Valerie M. Weaver, Marcus B. Smolka, Paul N. Span, Jan Lammerding

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)4211-4230
Number of pages20
JournalOncogene
Volume41
Issue number36
DOIs
StatePublished - Sep 2 2022

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Cancer Research

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