Dataset Information

Plectin-mediated cytoskeletal crosstalk as a target for inhibition of hepatocellular carcinoma growth and metastasis – in vitro phosphoproteomics

ABSTRACT: The most common primary malignancy of the liver, hepatocellular carcinoma (HCC), is a heterogeneous tumor entity with high metastatic potential and complex pathophysiology. Increasing evidence suggests that tissue mechanics plays a critical role in tumor onset and progression. Here we show that plectin, a major cytoskeletal crosslinker protein, plays a crucial role in mechanical homeostasis and mechanosensitive oncogenic signaling that drives hepatocarcinogenesis. Our expression analyses revealed elevated plectin levels in liver tumors, which correlated with poor prognosis for HCC patients. Using autochthonous and orthotopic mouse models we demonstrated that genetic and pharmacological inactivation of plectin potently suppressed the initiation and growth of HCC. Moreover, plectin targeting potently inhibited the invasion potential of human HCC cells and reduced their metastatic outgrowth in the lung. Proteomic and phosphoproteomic profiling linked plectin-dependent disruption of cytoskeletal networks to attenuation of oncogenic FAK, MAPK/Erk, and PI3K/AKT signatures. Importantly, by combining cell line-based and murine HCC models, we show that plectin inhibitor plecstatin-1 (PST) is well-tolerated and potently inhibits HCC progression. In conclusion, our study demonstrates that plectin-controlled cytoarchitecture is a key determinant of HCC development and suggests that pharmacologically induced disruption of mechanical homeostasis may represent a new therapeutic strategy for HCC treatment.

INSTRUMENT(S): timsTOF Pro

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Hepatoma Cell Line, Snu-475 Cell

DISEASE(S): Hepatocellular Carcinoma

SUBMITTER: Christopher Gerner

LAB HEAD: Christopher Gerner

PROVIDER: PXD060083 | Pride | 2025-04-22

REPOSITORIES: Pride

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			Action	DRS
	20-Phos-2136_BE6_1_3549.d.rar	Other
	20-Phos-2137_BE7_1_3550.d.rar	Other
	20-Phos-2138_BE8_1_3551.d.rar	Other
	20-Phos-2139_GA1_1_3553.d.rar	Other
	20-Phos-2140_GA2_1_3554.d.rar	Other

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Plectin-mediated cytoskeletal crosstalk as a target for inhibition of hepatocellular carcinoma growth and metastasis.

Outla Zuzana Z Oyman-Eyrilmez Gizem G Korelova Katerina K Prechova Magdalena M Frick Lukas L Sarnova Lenka L Bisht Piyush P Novotna Petra P Kosla Jan J Bortel Patricia P Borutzki Yasmin Y Bileck Andrea A Gerner Christopher C Rahbari Mohammad M Rahbari Nuh N Birgin Emrullah E Kvasnicova Bibiana B Galisova Andrea A Sulkova Katerina K Bauer Andreas A Jobe Njainday N Tolde Ondrej O Sticova Eva E Rösel Daniel D O'Connor Tracy T Otahal Martin M Jirak Daniel D Heikenwälder Mathias M Wiche Gerhard G Meier-Menches Samuel M SM Gregor Martin M

eLife 20250307

The most common primary malignancy of the liver, hepatocellular carcinoma (HCC), is a heterogeneous tumor entity with high metastatic potential and complex pathophysiology. Increasing evidence suggests that tissue mechanics plays a critical role in tumor onset and progression. Here, we show that plectin, a major cytoskeletal crosslinker protein, plays a crucial role in mechanical homeostasis and mechanosensitive oncogenic signaling that drives hepatocarcinogenesis. Our expression analyses reveal ...[more]

PMID: 40052672

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