Connexins orchestrate progression of breast cancer metastasis to the brain by promoting FAK activation

Lorusso, Girieca; Wyss, Christof B.; Kuonen, François; Vannini, Nicola; Billottet, Clotilde; Duffey, Nathalie; Pineau, Raphaël; Lan, Qiang; Wirapati, Pratyaksha; Barras, David; Tancredi, Alessandro; Lyck, Ruth; Lehr, Hans‐Anton; Engelhardt, Britta; Delorenzi, Mauro; Bikfalvi, Andréas; Rüegg, Curzio

doi:10.1126/scitranslmed.aax8933

Cited by 16 publications

(6 citation statements)

References 83 publications

(116 reference statements)

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“…Laminin gamma 2 chain (LAMC2) is one laminin chain [ 6 ] that is abnormally expressed in pancreatic [ 7 ], gastric [ 8 ], oral [ 9 ], lung [ 10 ], cervical [ 11 ], esophageal [ 12 ], and thyroid cancer [ 13 ]. Increasing evidence indicates that the high invasive potential and distant metastasis of tumor cells is dependent on LAMC2 expression, which is closely associated with tumor metastasis, recurrence, and patient mortality [ 14 – 16 ]. Since studies investigating the involvement of LAMC2 in OSCC are still in the initial stages, the specific mechanism by which LAMC2 affects the biological behavior of OSCC has not been fully elucidated [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

LAMC2 regulates proliferation, migration, and invasion mediated by the Pl3K/AKT/mTOR pathway in oral squamous carcinoma

Shan¹,

Liang²,

Feng³

et al. 2023

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Background Oral squamous cell carcinoma (OSCC) is a common malignant tumor. Recently, Laminin Gamma 2 (LAMC2) has been shown to be abnormally expressed in OSCC; however, how LAMC2 signaling contributes to the occurrence and development of OSCC and the role of autophagy in OSCC has not been fully explored. This study aimed to analyze the role and mechanism of LAMC2 signaling in OSCC and the involvement of autophagy in OSCC. Methods To explore the mechanism by which LAMC2 is highly expressed in OSCC, we used small interfering RNA (siRNA) to knock down LAMC2 to further observe the changes in the signaling pathway. Furthermore, we used cell proliferation assays, Transwell invasion assays, and wound-healing assays to observe the changes in OSCC proliferation, invasion, and metastasis. RFP-LC3 was used to detect the level of autophagy intensity. A cell line-derived xenograft (CDX) model was used to detect the effect of LAMC2 on tumor growth in vivo . Results This study found that the level of autophagy was correlated with the biological behavior of OSCC. The downregulation of LAMC2 activated autophagy and inhibited OSCC proliferation, invasion, and metastasis via inhibiting the PI3K/AKT/mTOR pathway. Moreover, autophagy has a dual effect on OSCC, and the synergistic downregulation of LAMC2 and autophagy can inhibit OSCC metastasis, invasion, and proliferation via the PI3K/AKT/mTOR pathway. Conclusions LAMC2 interacts with autophagy to regulate OSCC metastasis, invasion, and proliferation via the PI3K/AKT/mTOR pathway. LAMC2 down-regulation can synergistically modulate autophagy to inhibit OSCC migration, invasion, and proliferation.

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Section: Introductionmentioning

confidence: 99%

LAMC2 regulates proliferation, migration, and invasion mediated by the Pl3K/AKT/mTOR pathway in oral squamous carcinoma

Shan¹,

Liang²,

Feng³

et al. 2023

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“…We propose that the ULK1/2‐PXN‐FAK/Src signaling node in the mechanotransduction pathway can be targeted to treat breast tumors. In fact, FAK inhibitors hold great promise for breast cancer treatment (Timbrell et al , 2021; Lorusso et al , 2022). As ULK1/2 agonists are now commercially available, augmenting ULK1/2 kinase activity may represent a new therapeutic avenue.…”

Section: Discussionmentioning

confidence: 99%

An ULK1/2‐PXN mechanotransduction pathway suppresses breast cancer cell migration

Liang,

Zhang,

et al. 2023

EMBO Reports

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The remodeling and stiffening of the extracellular matrix (ECM) is a well‐recognized modulator of breast cancer progression. How changes in the mechanical properties of the ECM are converted into biochemical signals that direct tumor cell migration and metastasis remain poorly characterized. Here, we describe a new role for the autophagy‐inducing serine/threonine kinases ULK1 and ULK2 in mechanotransduction. We show that ULK1/2 activity inhibits the assembly of actin stress fibers and focal adhesions (FAs) and as a consequence impedes cell contraction and migration, independent of its role in autophagy. Mechanistically, we identify PXN/paxillin, a key component of the mechanotransducing machinery, as a direct binding partner and substrate of ULK1/2. ULK‐mediated phosphorylation of PXN at S32 and S119 weakens homotypic interactions and liquid–liquid phase separation of PXN, impairing FA assembly, which in turn alters the mechanical properties of breast cancer cells and their response to mechanical stimuli. ULK1/2 and the well‐characterized PXN regulator, FAK/Src, have opposing functions on mechanotransduction and compete for phosphorylation of adjacent serine and tyrosine residues. Taken together, our study reveals ULK1/2 as important regulator of PXN‐dependent mechanotransduction.

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“…We propose that the ULK1/2-PXN-FAK/Src signaling node in the mechanotransduction pathway can be targeted to treat breast tumors. In fact, FAK inhibitors hold great promise for breast cancer treatment (Lorusso et al, 2022; Timbrell et al, 2021). As ULK1/2 agonists are now commercially available, augmenting ULK1/2 kinase activity may represent a new therapeutic avenue.…”

Section: Discussionmentioning

confidence: 99%

An ULK1/2-PXN mechanotransduction complex suppresses breast cancer cell migration

Liang

Zhang

et al. 2023

Preprint

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The remodeling and stiffening of the extracellular matrix (ECM) associated with breast cancers is a well-recognized modulator of disease progression. However, how changes in the mechanical properties of the ECM are converted into biochemical signals that direct tumor cell migration and metastasis remains poorly characterized. Here, we describe a new role for the autophagy-inducing serine/threonine kinases ULK1 and ULK2 in mechanotransduction. We demonstrate that ULK1/2 activity inhibits the assembly of actin stress fibers and focal adhesions (FAs), and as a consequence impedes cell contraction and migration. Mechanistically, we identify PXN/paxillin, a key component of the mechanotransducing machinery, as a direct binding partner and substrate of ULK1/2. ULK-mediated phosphorylation of PXN at S32 and S119 weakens homotypic interactions and liquid-liquid phase separation of PXN, impairing FA assembly, which in turn impedes the mechanotransduction of breast cancer cells. ULK1/2 and the well characterized PXN regulator, FAK/Src, have opposing functions on mechanotransduction and compete for phosphorylation of adjacent serine and tyrosine residues. Thus, our study reveals ULK1/2 as important regulators of PXN-dependent mechanotransduction.

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Connexins orchestrate progression of breast cancer metastasis to the brain by promoting FAK activation

Cited by 16 publications

References 83 publications

LAMC2 regulates proliferation, migration, and invasion mediated by the Pl3K/AKT/mTOR pathway in oral squamous carcinoma

LAMC2 regulates proliferation, migration, and invasion mediated by the Pl3K/AKT/mTOR pathway in oral squamous carcinoma

An ULK1/2‐PXN mechanotransduction pathway suppresses breast cancer cell migration

An ULK1/2-PXN mechanotransduction complex suppresses breast cancer cell migration

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