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.
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References
de Las Heras JI, Schirmer EC. The nuclear envelope and cancer: a diagnostic perspective and historical overview. Adv Exp Med Biol. 2014;773:5–26.
Caille N, Thoumine O, Tardy Y, Meister JJ. Contribution of the nucleus to the mechanical properties of endothelial cells. J Biomech. 2002;35:177–87.
Guilak F, Tedrow JR, Burgkart R. Viscoelastic properties of the cell nucleus. Biochem Biophys Res Commun. 2000;269:781–6.
Denais C, Lammerding J. Nuclear mechanics in cancer. Adv Exp Med Biol. 2014;773:435–70.
Tseng Y, Lee JS, Kole TP, Jiang I, Wirtz D. Micro-organization and visco-elasticity of the interphase nucleus revealed by particle nanotracking. J Cell Sci. 2004;117:2159–67.
Wolf K, Te Lindert M, Krause M, Alexander S, Te Riet J, Willis AL, et al. Physical limits of cell migration: control by ECM space and nuclear deformation and tuning by proteolysis and traction force. J Cell Biol. 2013;201:1069–84.
Stoitzner P, Pfaller K, Stossel H, Romani N. A close-up view of migrating Langerhans cells in the skin. J Investig Dermatol. 2002;118:117–25.
Weigelin B, Bakker GJ, Friedl P. Intravital third harmonic generation microscopy of collective melanoma cell invasion. IntraVital. 2012;1:32–43.
Doerschuk CM, Beyers N, Coxson HO, Wiggs B, Hogg JC. Comparison of neutrophil and capillary diameters and their relation to neutrophil sequestration in the lung. J Appl Physiol. 1993;74:3040–5.
Davidson PM, Denais C, Bakshi MC, Lammerding J. Nuclear deformability constitutes a rate-limiting step during cell migration in 3-D environments. Cell Mol Bioeng. 2014;7:293–306.
Harada T, Swift J, Irianto J, Shin JW, Spinler KR, Athirasala A, et al. Nuclear lamin stiffness is a barrier to 3D migration, but softness can limit survival. J Cell Biol. 2014;204:669–82.
Lautscham LA, Kammerer C, Lange JR, Kolb T, Mark C, Schilling A, et al. Migration in confined 3D environments is determined by a combination of adhesiveness, nuclear volume, contractility, and cell stiffness. Biophys J. 2015;109:900–13.
Mukherjee A, Barai A, Singh RK, Yan W, Sen S. Nuclear plasticity increases susceptibility to damage during confined migration. PLoS Comput Biol. 2020;16:e1008300.
Bustin M, Misteli T. Nongenetic functions of the genome. Science. 2016;352:aad6933.
Reddy KL, Feinberg AP. Higher order chromatin organization in cancer. Semin Cancer Biol. 2013;23:109–15.
Bell ES, Lammerding J. Causes and consequences of nuclear envelope alterations in tumour progression. Eur J Cell Biol. 2016;95:449–64.
Irianto J, Pfeifer CR, Ivanovska IL, Swift J, Discher D. Nuclear lamins in cancer. Cell Mol Bioeng. 2016;9:258–67.
Pombo A, Dillon N. Three-dimensional genome architecture: players and mechanisms. Nat Rev Mol Cell Biol. 2015;16:245–57.
Hetzer MW. The nuclear envelope. Cold Spring Harb Perspect Biol. 2010;2:a000539.
Stephens AD, Banigan EJ, Adam SA, Goldman RD, Marko JF. Chromatin and lamin A determine two different mechanical response regimes of the cell nucleus. Mol Biol Cell. 2017;28:1984–96.
Stephens AD, Liu PZ, Banigan EJ, Almassalha LM, Backman V, Adam SA, et al. Chromatin histone modifications and rigidity affect nuclear morphology independent of lamins. Mol Biol Cell. 2018;29:220–33.
Schape J, Prausse S, Radmacher M, Stick R. Influence of lamin A on the mechanical properties of amphibian oocyte nuclei measured by atomic force microscopy. Biophys J. 2009;96:4319–25.
Swift J, Ivanovska IL, Buxboim A, Harada T, Dingal PC, Pinter J, et al. Nuclear lamin-A scales with tissue stiffness and enhances matrix-directed differentiation. Science. 2013;341:1240104.
Lammerding J, Fong LG, Ji JY, Reue K, Stewart CL, Young SG, et al. Lamins A and C but not lamin B1 regulate nuclear mechanics. J Biol Chem. 2006;281:25768–80.
Lammerding J, Schulze PC, Takahashi T, Kozlov S, Sullivan T, Kamm RD, et al. Lamin A/C deficiency causes defective nuclear mechanics and mechanotransduction. J Clin Investig. 2004;113:370–8.
Zwerger M, Jaalouk DE, Lombardi ML, Isermann P, Mauermann M, Dialynas G, et al. Myopathic lamin mutations impair nuclear stability in cells and tissue and disrupt nucleo-cytoskeletal coupling. Hum Mol Genet. 2013;22:2335–49.
Earle AJ, Kirby TJ, Fedorchak GR, Isermann P, Patel J, Iruvanti S, et al. Mutant lamins cause nuclear envelope rupture and DNA damage in skeletal muscle cells. Nat Mater. 2020;19:464–73.
Cho S, Vashisth M, Abbas A, Majkut S, Vogel K, Xia Y, et al. Mechanosensing by the lamina protects against nuclear rupture, DNA damage, and cell-cycle arrest. Dev Cell. 2019;49:920–35.e5.
Vargas JD, Hatch EM, Anderson DJ, Hetzer MW. Transient nuclear envelope rupturing during interphase in human cancer cells. Nucleus. 2012;3:88–100.
Denais CM, Gilbert RM, Isermann P, McGregor AL, Te Lindert M, Weigelin B, et al. Nuclear envelope rupture and repair during cancer cell migration. Science. 2016;352:353–8.
Raab M, Gentili M, de Belly H, Thiam HR, Vargas P, Jimenez AJ, et al. ESCRT III repairs nuclear envelope ruptures during cell migration to limit DNA damage and cell death. Science. 2016;352:359–62.
Mitchell MJ, Denais C, Chan MF, Wang Z, Lammerding J, King MR. Lamin A/C deficiency reduces circulating tumor cell resistance to fluid shear stress. Am J Physiol Cell Physiol. 2015;309:C736–46.
Gruenbaum Y, Foisner R. Lamins: nuclear intermediate filament proteins with fundamental functions in nuclear mechanics and genome regulation. Annu Rev Biochem. 2015;84:131–64.
Andres V, Gonzalez JM. Role of A-type lamins in signaling, transcription, and chromatin organization. J Cell Biol. 2009;187:945–57.
Maurer M, Lammerding J. The driving force: nuclear mechanotransduction in cellular function, fate, and disease. Annu Rev Biomed Eng. 2019;21:443–68.
Schreiber KH, Kennedy BK. When lamins go bad: nuclear structure and disease. Cell. 2013;152:1365–75.
Wong X, Stewart CL. The laminopathies and the insights they provide into the structural and functional organization of the nucleus. Annu Rev Genomics Hum Genet. 2020;21:263–88.
Dubik N, Mai S. Lamin A/C: function in normal and tumor cells. Cancers. 2020;12:3688.
Alhudiri IM, Nolan CC, Ellis IO, Elzagheid A, Rakha EA, Green AR, et al. Expression of Lamin A/C in early-stage breast cancer and its prognostic value. Breast Cancer Res Treat. 2019;174:661–8.
Matsumoto A, Hieda M, Yokoyama Y, Nishioka Y, Yoshidome K, Tsujimoto M, et al. Global loss of a nuclear lamina component, lamin A/C, and LINC complex components SUN1, SUN2, and nesprin-2 in breast cancer. Cancer Med. 2015;4:1547–57.
Wazir U, Ahmed MH, Bridger JM, Harvey A, Jiang WG, Sharma AK, et al. The clinicopathological significance of lamin A/C, lamin B1 and lamin B receptor mRNA expression in human breast cancer. Cell Mol Biol Lett. 2013;18:595–611.
Capo-chichi CD, Cai KQ, Smedberg J, Ganjei-Azar P, Godwin AK, Xu XX. Loss of A-type lamin expression compromises nuclear envelope integrity in breast cancer. Chin J Cancer. 2011;30:415–25.
Onitilo AA, Engel JM, Greenlee RT, Mukesh BN. Breast cancer subtypes based on ER/PR and Her2 expression: comparison of clinicopathologic features and survival. Clin Med Res. 2009;7:4–13.
Sorlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H, et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci USA. 2001;98:10869–74.
Davidson PM, Fedorchak GR, Mondesert-Deveraux S, Bell ES, Isermann P, Aubry D, et al. High-throughput microfluidic micropipette aspiration device to probe time-scale dependent nuclear mechanics in intact cells. Lab Chip. 2019;19:3652–63.
Saleh T, Alhesa A, El-Sadoni M, Abu Shahin N, Alsharaiah E, Al Shboul S, et al. The expression of the senescence-associated biomarker Lamin B1 in human breast cancer. Diagnostics. 2020;12:609.
Stewart C, Burke B. Teratocarcinoma stem cells and early mouse embryos contain only a single major lamin polypeptide closely resembling lamin B. Cell. 1987;51:383–92.
Bussolati G, Maletta F, Asioli S, Annaratone L, Sapino A, Marchio C. “To be or not to be in a good shape”: diagnostic and clinical value of nuclear shape irregularities in thyroid and breast cancer. Adv Exp Med Biol. 2014;773:101–21.
Pajerowski JD, Dahl KN, Zhong FL, Sammak PJ, Discher DE. Physical plasticity of the nucleus in stem cell differentiation. Proc Natl Acad Sci USA. 2007;104:15619–24.
Wang X, Liu H, Zhu M, Cao C, Xu Z, Tsatskis Y, et al. Mechanical stability of the cell nucleus—roles played by the cytoskeleton in nuclear deformation and strain recovery. J Cell Sci. 2018;131:jcs209627.
Lee H, Adams WJ, Alford PW, McCain ML, Feinberg AW, Sheehy SP, et al. Cytoskeletal prestress regulates nuclear shape and stiffness in cardiac myocytes. Exp Biol Med. 2015;240:1543–54.
McGregor AL, Hsia CR, Lammerding J. Squish and squeeze-the nucleus as a physical barrier during migration in confined environments. Curr Opin Cell Biol. 2016;40:32–40.
Davidson PM, Sliz J, Isermann P, Denais C, Lammerding J. Design of a microfluidic device to quantify dynamic intra-nuclear deformation during cell migration through confining environments. Integr Biol. 2015;7:1534–46.
Guy CT, Cardiff RD, Muller WJ. Induction of mammary tumors by expression of polyomavirus middle T oncogene: a transgenic mouse model for metastatic disease. Mol Cell Biol. 1992;12:954–61.
Borowsky AD, Namba R, Young LJ, Hunter KW, Hodgson JG, Tepper CG, et al. Syngeneic mouse mammary carcinoma cell lines: two closely related cell lines with divergent metastatic behavior. Clin Exp Metastasis. 2005;22:47–59.
Mekhdjian AH, Kai F, Rubashkin MG, Prahl LS, Przybyla LM, McGregor AL, et al. Integrin-mediated traction force enhances paxillin molecular associations and adhesion dynamics that increase the invasiveness of tumor cells into a three-dimensional extracellular matrix. Mol Biol Cell. 2017;28:1467–88.
Sahai E. Illuminating the metastatic process. Nat Rev Cancer. 2007;7:737–49.
Aslakson CJ, Miller FR. Selective events in the metastatic process defined by analysis of the sequential dissemination of subpopulations of a mouse mammary tumor. Cancer Res. 1992;52:1399–405.
Dexter DL, Kowalski HM, Blazar BA, Fligiel Z, Vogel R, Heppner GH. Heterogeneity of tumor cells from a single mouse mammary tumor. Cancer Res. 1978;38:3174–81.
Lelekakis M, Moseley JM, Martin TJ, Hards D, Williams E, Ho P, et al. A novel orthotopic model of breast cancer metastasis to bone. Clin Exp Metastasis. 1999;17:163–70.
de Leeuw R, Gruenbaum Y, Medalia O. Nuclear lamins: thin filaments with major functions. Trends Cell Biol. 2018;28:34–45.
Szklarczyk D, Gable AL, Lyon D, Junge A, Wyder S, Huerta-Cepas J, et al. STRING v11: protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets. Nucleic Acids Res. 2019;47:D607–13.
Bertacchini J, Beretti F, Cenni V, Guida M, Gibellini F, Mediani L, et al. The protein kinase Akt/PKB regulates both prelamin A degradation and Lmna gene expression. FASEB J. 2013;27:2145–55.
Lloyd DJ, Trembath RC, Shackleton S. A novel interaction between lamin A and SREBP1: implications for partial lipodystrophy and other laminopathies. Hum Mol Genet. 2002;11:769–77.
Okumura K, Hosoe Y, Nakajima N. c-Jun and Sp1 family are critical for retinoic acid induction of the lamin A/C retinoic acid-responsive element. Biochem Biophys Res Commun. 2004;320:487–92.
Mymrikov EV, Seit-Nebi AS, Gusev NB. Large potentials of small heat shock proteins. Physiol Rev. 2011;91:1123–59.
Batulan Z, Pulakazhi Venu VK, Li Y, Koumbadinga G, Alvarez-Olmedo DG, Shi C, et al. Extracellular release and signaling by heat shock protein 27: role in modifying vascular inflammation. Front Immunol. 2016;7:285.
Sugiyama Y, Suzuki A, Kishikawa M, Akutsu R, Hirose T, Waye MM, et al. Muscle develops a specific form of small heat shock protein complex composed of MKBP/HSPB2 and HSPB3 during myogenic differentiation. J Biol Chem. 2000;275:1095–104.
Isermann P, Lammerding J. Nuclear mechanics and mechanotransduction in health and disease. Curr Biol. 2013;23:R1113–21.
Buxboim A, Swift J, Irianto J, Spinler KR, Dingal PC, Athirasala A, et al. Matrix elasticity regulates lamin-A,C phosphorylation and turnover with feedback to actomyosin. Curr Biol. 2014;24:1909–17.
Peter M, Nakagawa J, Doree M, Labbe JC, Nigg EA. In vitro disassembly of the nuclear lamina and M phase-specific phosphorylation of lamins by cdc2 kinase. Cell. 1990;61:591–602.
Collas P. Sequential PKC- and Cdc2-mediated phosphorylation events elicit zebrafish nuclear envelope disassembly. J Cell Sci. 1999;112:977–87.
Barati MT, Rane MJ, Klein JB, McLeish KR. A proteomic screen identified stress-induced chaperone proteins as targets of Akt phosphorylation in mesangial cells. J Proteome Res. 2006;5:1636–46.
Cenni V, Bertacchini J, Beretti F, Lattanzi G, Bavelloni A, Riccio M, et al. Lamin A Ser404 is a nuclear target of Akt phosphorylation in C2C12 cells. J Proteome Res. 2008;7:4727–35.
Naeem AS, Zhu Y, Di WL, Marmiroli S, O’Shaughnessy RF. AKT1-mediated lamin A/C degradation is required for nuclear degradation and normal epidermal terminal differentiation. Cell Death Differ. 2015;22:2123–32.
Fruman DA, Rommel C. PI3K and cancer: lessons, challenges and opportunities. Nat Rev Drug Discov. 2014;13:140–56.
Wennemers M, Stegeman H, Bussink J, Versleijen-Jonkers YM, van Laarhoven HW, Raleigh JA, et al. Hypoxia regulation of phosphokinases and the prognostic value of pAKT in breast cancer. Int J Biol Markers. 2013;28:151–60.
Rhodes N, Heerding DA, Duckett DR, Eberwein DJ, Knick VB, Lansing TJ, et al. Characterization of an Akt kinase inhibitor with potent pharmacodynamic and antitumor activity. Cancer Res. 2008;68:2366–74.
Han EK, Leverson JD, McGonigal T, Shah OJ, Woods KW, Hunter T, et al. Akt inhibitor A-443654 induces rapid Akt Ser-473 phosphorylation independent of mTORC1 inhibition. Oncogene. 2007;26:5655–61.
Maira SM, Pecchi S, Huang A, Burger M, Knapp M, Sterker D, et al. Identification and characterization of NVP-BKM120, an orally available pan-class I PI3-kinase inhibitor. Mol Cancer Ther. 2012;11:317–28.
Agrelo R, Setien F, Espada J, Artiga MJ, Rodriguez M, Perez-Rosado A, et al. Inactivation of the lamin A/C gene by CpG island promoter hypermethylation in hematologic malignancies, and its association with poor survival in nodal diffuse large B-cell lymphoma. J Clin Oncol. 2005;23:3940–7.
Marmiroli S, Bertacchini J, Beretti F, Cenni V, Guida M, De Pol A, et al. A-type lamins and signaling: the PI 3-kinase/Akt pathway moves forward. J Cell Physiol. 2009;220:553–61.
Nagelkerke A, van Kuijk SJ, Sweep FC, Nagtegaal ID, Hoogerbrugge N, Martens JW, et al. Constitutive expression of gamma-H2AX has prognostic relevance in triple negative breast cancer. Radiother Oncol. 2011;101:39–45.
Cho S, Irianto J, Discher DE. Mechanosensing by the nucleus: From pathways to scaling relationships. J Cell Biol. 2017;216:305–15.
Gonzalez-Cruz RD, Sadick JS, Fonseca VC, Darling EM. Nuclear lamin protein C is linked to lineage-specific, whole-cell mechanical properties. Cell Mol Bioeng. 2018;11:131–42.
Ortega MA, Fraile-Martinez O, Asunsolo A, Bujan J, Garcia-Honduvilla N, Coca S. Signal transduction pathways in breast cancer: the important role of PI3K/Akt/mTOR. J Oncol. 2020;2020:9258396.
Broers JL, Machiels BM, Kuijpers HJ, Smedts F, van den Kieboom R, Raymond Y, et al. A- and B-type lamins are differentially expressed in normal human tissues. Histochem Cell Biol. 1997;107:505–17.
Ivorra C, Kubicek M, Gonzalez JM, Sanz-Gonzalez SM, Alvarez-Barrientos A, O’Connor JE, et al. A mechanism of AP-1 suppression through interaction of c-Fos with lamin A/C. Genes Dev. 2006;20:307–20.
Nitta RT, Jameson SA, Kudlow BA, Conlan LA, Kennedy BK. Stabilization of the retinoblastoma protein by A-type nuclear lamins is required for INK4A-mediated cell cycle arrest. Mol Cell Biol. 2006;26:5360–72.
Van Berlo JH, Voncken JW, Kubben N, Broers JL, Duisters R, van Leeuwen RE, et al. A-type lamins are essential for TGF-beta1 induced PP2A to dephosphorylate transcription factors. Hum Mol Genet. 2005;14:2839–49.
Johnson BR, Nitta RT, Frock RL, Mounkes L, Barbie DA, Stewart CL, et al. A-type lamins regulate retinoblastoma protein function by promoting subnuclear localization and preventing proteasomal degradation. Proc Natl Acad Sci USA. 2004;101:9677–82.
Aljada A, Doria J, Saleh AM, Al-Matar SH, AlGabbani S, Shamsa HB, et al. Altered Lamin A/C splice variant expression as a possible diagnostic marker in breast cancer. Cell Oncol. 2016;39:161–74.
Belt EJ, Fijneman RJ, van den Berg EG, Bril H, Delis-van Diemen PM, Tijssen M, et al. Loss of lamin A/C expression in stage II and III colon cancer is associated with disease recurrence. Eur J Cancer. 2011;47:1837–45.
Wu Z, Wu L, Weng D, Xu D, Geng J, Zhao F. Reduced expression of lamin A/C correlates with poor histological differentiation and prognosis in primary gastric carcinoma. J Exp Clin Cancer Res. 2009;28:8.
Coradeghini R, Barboro P, Rubagotti A, Boccardo F, Parodi S, Carmignani G, et al. Differential expression of nuclear lamins in normal and cancerous prostate tissues. Oncol Rep. 2006;15:609–13.
Willis ND, Cox TR, Rahman-Casans SF, Smits K, Przyborski SA, van den Brandt P, et al. Lamin A/C is a risk biomarker in colorectal cancer. PLoS ONE. 2008;3:e2988.
Gong G, Chen P, Li L, Tan H, Zhou J, Zhou Y, et al. Loss of lamin A but not lamin C expression in epithelial ovarian cancer cells is associated with metastasis and poor prognosis. Pathol Res Pract. 2015;211:175–82.
Venables RS, McLean S, Luny D, Moteleb E, Morley S, Quinlan RA, et al. Expression of individual lamins in basal cell carcinomas of the skin. Br J Cancer. 2001;84:512–9.
Shimi T, Pfleghaar K, Kojima S, Pack CG, Solovei I, Goldman AE, et al. The A- and B-type nuclear lamin networks: microdomains involved in chromatin organization and transcription. Genes Dev. 2008;22:3409–21.
Fong LG, Ng JK, Lammerding J, Vickers TA, Meta M, Cote N, et al. Prelamin A and lamin A appear to be dispensable in the nuclear lamina. J Clin Investig. 2006;116:743–52.
Sullivan T, Escalante-Alcalde D, Bhatt H, Anver M, Bhat N, Nagashima K, et al. Loss of A-type lamin expression compromises nuclear envelope integrity leading to muscular dystrophy. J Cell Biol. 1999;147:913–20.
Kennedy BK, Pennypacker JK. RB and lamins in cell cycle regulation and aging. Adv Exp Med Biol. 2014;773:127–42.
Redwood AB, Perkins SM, Vanderwaal RP, Feng Z, Biehl KJ, Gonzalez-Suarez I, et al. A dual role for A-type lamins in DNA double-strand break repair. Cell Cycle. 2011;10:2549–60.
Maynard S, Keijzers G, Akbari M, Ezra MB, Hall A, Morevati M, et al. Lamin A/C promotes DNA base excision repair. Nucleic Acids Res. 2019;47:11709–28.
Gonzalo S. DNA damage and lamins. Adv Exp Med Biol. 2014;773:377–99.
Frock RL, Kudlow BA, Evans AM, Jameson SA, Hauschka SD, Kennedy BK. Lamin A/C and emerin are critical for skeletal muscle satellite cell differentiation. Genes Dev. 2006;20:486–500.
Hoxhaj G, Manning BD. The PI3K-AKT network at the interface of oncogenic signalling and cancer metabolism. Nat Rev Cancer. 2020;20:74–88.
Ali R, Wendt MK. The paradoxical functions of EGFR during breast cancer progression. Signal Transduct Target Ther. 2017;2:16042.
Brady CA, Attardi LD. p53 at a glance. J Cell Sci. 2010;123:2527–32.
Concin N, Zeillinger C, Tong D, Stimpfl M, Konig M, Printz D, et al. Comparison of p53 mutational status with mRNA and protein expression in a panel of 24 human breast carcinoma cell lines. Breast Cancer Res Treat. 2003;79:37–46.
Condor M, Mark C, Gerum RC, Grummel NC, Bauer A, Garcia-Aznar JM, et al. Breast cancer cells adapt contractile forces to overcome steric hindrance. Biophys J. 2019;116:1305–12.
Shah P, Hobson CM, Cheng S, Colville MJ, Paszek MJ, Superfine R, et al. Nuclear deformation causes DNA damage by increasing replication stress. Curr Biol. 2021;31:753–65.e6.
Irianto J, Pfeifer CR, Bennett RR, Xia Y, Ivanovska IL, Liu AJ, et al. Nuclear constriction segregates mobile nuclear proteins away from chromatin. Mol Biol Cell. 2016;27:4011–20.
Roncato F, Regev O, Feigelson SW, Yadav SK, Kaczmarczyk L, Levi N, et al. Reduced lamin A/C does not facilitate cancer cell transendothelial migration but compromises lung metastasis. Cancers. 2021;13:2383.
Pickup MW, Laklai H, Acerbi I, Owens P, Gorska AE, Chytil A, et al. Stromally derived lysyl oxidase promotes metastasis of transforming growth factor-beta-deficient mouse mammary carcinomas. Cancer Res. 2013;73:5336–46.
Miroshnikova YA, Mouw JK, Barnes JM, Pickup MW, Lakins JN, Kim Y, et al. Tissue mechanics promote IDH1-dependent HIF1alpha-tenascin C feedback to regulate glioblastoma aggression. Nat Cell Biol. 2016;18:1336–45.
Hanson PI, Roth R, Lin Y, Heuser JE. Plasma membrane deformation by circular arrays of ESCRT-III protein filaments. J Cell Biol. 2008;180:389–402.
Guz N, Dokukin M, Kalaparthi V, Sokolov I. If cell mechanics can be described by elastic modulus: study of different models and probes used in indentation experiments. Biophys J. 2014;107:564–75.
Schindelin J, Arganda-Carreras I, Frise E, Kaynig V, Longair M, Pietzsch T, et al. Fiji: an open-source platform for biological-image analysis. Nat Methods. 2012;9:676–82.
Bastos de Oliveira FM, Kim D, Cussiol JR, Das J, Jeong MC, Doerfler L, et al. Phosphoproteomics reveals distinct modes of Mec1/ATR signaling during DNA replication. Mol Cell. 2015;57:1124–32.
Bastos de Oliveira FM, Kim D, Lanz M, Smolka MB. Quantitative analysis of DNA damage signaling responses to chemical and genetic perturbations. Methods Mol Biol. 2018;1672:645–60.
Kim D, Liu Y, Oberly S, Freire R, Smolka MB. ATR-mediated proteome remodeling is a major determinant of homologous recombination capacity in cancer cells. Nucleic Acids Res. 2018;46:8311–25.
R_Core_Team. R: A language and environment for statistical computing. Vienna, Austria: R Foundation for Statistical Computing; 2021. https://www.R-project.org/.
Love MI, Huber W, Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 2014;15:550.
Kassambara A. ggpubr: ‘ggplot2’ Based Publication Ready Plots. R package version 040. 2020. https://CRAN.R-project.org/package=ggpubr.
Kramer A, Green J, Pollard J Jr., Tugendreich S. Causal analysis approaches in Ingenuity Pathway Analysis. Bioinformatics. 2014;30:523–30.
Acknowledgements
We thank Prof. Peter Friedl for the 4T1 progression series cell lines. This work was performed in part at the Cornell NanoScale Science & Technology Facility, a member of the National Nanotechnology Coordinated Infrastructure, which is supported by the National Science Foundation (Grant NNCI-2025233). The content of this paper is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The results published here are in part based upon data generated by the TCGA Research Network: https://www.cancer.gov/tcga.
Funding
This work was supported by funding from the National Institutes of Health (R01 HL082792, R01 GM137605, U54 CA210184, and U54 CA193461 to JL, R35 GM141159 and R01 GM123018 to MBS), the Department of Defense Breast Cancer Research Program (Breakthrough Award BC150580 to JL), and the National Science Foundation (CAREER Award CBET-1254846 to JL and Graduate Research Fellowship DGE-1144153 to ALM). This work was performed in part at the Cornell NanoScale Science & Technology Facility (CNF), a member of the National Nanotechnology Coordinated Infrastructure NNCI), which is supported by the National Science Foundation (Grant NNCI-2025233).
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ESB and JL conceptualized and designed the experiments; JL supervised the research; ESB, PS, NZS, AAV, JLPM, and ALM performed experiments and analyzed data; DK and MS performed the SILAC proteomic analysis; PI, JJE, PMD, JNL, and VMW contributed to the development of resources, including constructs, cell lines, assays, and/or image analysis methods; PNS and LV contributed human breast tumor tissue samples and analysis; EB and JL wrote the paper; all authors contributed to the editing of the paper; and JL and MBS acquired funding.
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JL has provided paid consulting services for BridgeBio for the role of lamins in unrelated projects.
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Bell, E.S., Shah, P., Zuela-Sopilniak, N. et al. Low lamin A levels enhance confined cell migration and metastatic capacity in breast cancer. Oncogene 41, 4211–4230 (2022). https://doi.org/10.1038/s41388-022-02420-9
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DOI: https://doi.org/10.1038/s41388-022-02420-9
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