Causes and consequences of nuclear envelope alterations in tumour progression

Abstract

Morphological changes in the size and shape of the nucleus are highly prevalent in cancer, but the underlying molecular mechanisms and the functional relevance remain poorly understood. Nuclear envelope proteins, which can modulate nuclear shape and organization, have emerged as key components in a variety of signalling pathways long implicated in tumourigenesis and metastasis. The expression of nuclear envelope proteins is altered in many cancers, and changes in levels of nuclear envelope proteins lamins A and C are associated with poor prognosis in multiple human cancers. In this review we highlight the role of the nuclear envelope in different processes important for tumour initiation and cancer progression, with a focus on lamins A and C. Lamin A/C controls many cellular processes with key roles in cancer, including cell invasion, stemness, genomic stability, signal transduction, transcriptional regulation, and resistance to mechanical stress. In addition, we discuss potential mechanisms mediating the changes in lamin levels observed in many cancers. A better understanding of cause-and-effect relationships between lamin expression and tumour progression could reveal important mechanisms for coordinated regulation of oncogenic processes, and indicate therapeutic vulnerabilities that could be exploited for improved patient outcome.

Promoter hypermethylation as a mechanism for Lamin A/C silencing in a subset of neuroblastoma cells

“…The lack of Lamin A/C expression in malignant B- and T-lymphocytes may reflect blockade of the differentiation pathway in these cells [32]. …”

Bursting the Bubble – Nuclear Envelope Rupture as a Path to Genomic Instability?

“…Lamin levels, especially those of lamin A/C, determine the stiffness of the nucleus and its susceptibility to mechanical strain [24, 37, 40]. Many cancers cells have substantial alterations in lamin A/C levels [43, 44]. Mutations in the lamin genes, particularly LMNA , cause a broad spectrum of diseases called laminopathies.…”

Nuclear envelope rupture drives genome instability in cancer

“…, 2012). This is perhaps unsurprising, considering that the nuclear envelope of cancer cells has long been known to be commonly structurally impaired (Bernhard and Granboulan, 1963; Bell and Lammerding, 2016). Indeed, as far back as 1860, abnormalities in nuclear size and shape were used to identify cells that had become cancerous (Beale, 1860).…”

“…One obvious explanation lies in the fact that cancer cells commonly exhibit aberrant expression of lamin proteins, which impairs the structural integrity of the nuclear lamina (Chow et al. , 2012; Ho and Lammerding, 2012; Bell and Lammerding, 2016; Vargas et al. , 2012).…”