Ligand-independent integrin β1 signaling supports lung adenocarcinoma development

Plosa, Erin J.; Kropski, Jonathan A.; Venton, Lindsay; Reddy, Anupama; Bock, Fabian; Chang, Betty; Luna, A.; Nabukhotna, Kateryna; Xu, Zhi-Qi; Prather, Rebecca A; Lee, Sharon; Tanjore, Harikrishna; Polosukhin, Vasiliy V.; Viquez, Olga M.; Jones, Angela; Luo, Wenguang; Wilson, Matthew H.; Rathmell, W. Kimryn; Massion, Pierre P.; Pozzi, Ambra; Blackwell, Timothy S.; Zent, Roy

doi:10.1172/jci.insight.154098

Cited by 10 publications

(5 citation statements)

References 51 publications

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“…These mice exhibited grossly normal airspace size at 3 months of age but also increased epithelial inflammation and tight junction defects paired with modest intraseptal edema ( 9 ). We confirmed sustained β 1 integrin expression in β 1 fl/fl littermate control mice and normal histology in SP-C rtTA TetO-Cre β 1 fl/fl mice not receiving doxycycline at 3 months of age ( 9 , 19 ). While doxycycline toxicity has been reported with embryonic administration ( 20 ), we observed no overt histologic or biological toxicity from the rtTA system or from doxycycline itself in this postdevelopmental model ( 9 ).…”

Section: Resultssupporting

confidence: 69%

“…To determine the role of epithelial β 1 integrin in alveolar repair after injury, we generated mice with a β 1 integrin deletion in AT2 cells in the adult lung utilizing the SP-C rtTA TetO-Cre doxycycline-inducible system ( 9 , 19 ) and floxed β 1 integrin (β 1 fl/fl ), hereafter referred to as β 1 AT2-KO mice. We previously reported the efficient deletion of β 1 integrin in AT2 cells (then termed β 1 rtTA mice).…”

Section: Resultsmentioning

confidence: 99%

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Alveolar repair following LPS-induced injury requires cell-ECM interactions

Sucre¹,

Bock²,

Negretti³

et al. 2023

JCI Insight

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During alveolar repair, alveolar type 2 (AT2) epithelial cell progenitors rapidly proliferate and differentiate into flat AT1 epithelial cells. Failure of normal alveolar repair mechanisms can lead to loss of alveolar structure (emphysema) or development of fibrosis, depending on the type and severity of injury. To test if β 1 -containing integrins are required during repair following acute injury, we administered E . coli lipopolysaccharide (LPS) by intratracheal injection to mice with a postdevelopmental deletion of β 1 integrin in AT2 cells. While control mice recovered from LPS injury without structural abnormalities, β 1 -deficient mice had more severe inflammation and developed emphysema. In addition, recovering alveoli were repopulated with an abundance of rounded epithelial cells coexpressing AT2 epithelial, AT1 epithelial, and mixed intermediate cell state markers, with few mature type 1 cells. AT2 cells deficient in β 1 showed persistently increased proliferation after injury, which was blocked by inhibiting NF-κB activation in these cells. Lineage tracing experiments revealed that β 1 -deficient AT2 cells failed to differentiate into mature AT1 epithelial cells. Together, these findings demonstrate that functional alveolar repair after injury with terminal alveolar epithelial differentiation requires β 1 -containing integrins.

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Section: Resultssupporting

confidence: 69%

Section: Resultsmentioning

confidence: 99%

Alveolar repair following LPS-induced injury requires cell-ECM interactions

Sucre¹,

Bock²,

Negretti³

et al. 2023

JCI Insight

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“…To determine the role of epithelial β1 integrin in alveolar repair after injury, we generated mice with a β1-integrin deletion in AT2 cells in the adult lung utilizing the SP-C–rtTA; TetO-Cre doxycycline-inducible system (9, 23) and floxed β1-integrin (β1 f/f ), hereafter referred to as β1 AT2-KO mice. We previously reported the efficient deletion of β1 integrin in AT2 cells and sustained β1 integrin expression in β1 f/f littermate control mice (then termed β1 rtTA mice) and confirmed normal histology in SP-C rtTA; TetO-Cre; β1 f/f mice not receiving doxycycline at three months of age (9, 23). While doxycycline toxicity has been reported with embryonic administration (24), we observed no overt histologic or biological toxicity from the rtTA system or from doxycycline itself in this post-developmental model (9).…”

Section: Resultsmentioning

confidence: 99%

Alveolar Repair Following Lipopolysaccharide-induced Injury Requires Cell-Extracellular Matrix Interactions

Sucre

Bock

Negretti

et al. 2022

Preprint

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β1 integrins are known to regulate lung development and homeostasis, however their role in lung epithelial repair is unclear. In this study, we challenged mice with a type 2 alveolar epithelial cell deletion of β1 integrin with a single dose of intratracheal lipopolysaccharide. These mice developed persistent inflammation, severe lung injury, and emphysema. The β1 integrin-deficient alveolus repaired by repopulating with overabundant large, round type 2 alveolar epithelial cells and reduced numbers of alveolar type 1 cells. These abnormal β1 integrin-deficient type 2 cells had significant actin cytoskeletal defects resulting in their inability to attain a flattened type 1 cell shape. In addition, terminal differentiation into type 1 and 2 alveolar epithelial cells was impaired as they expressed both type 2 and intermediate cell markers. Thus, β1 integrin plays a key role in alveolar repair by regulating the cell-shape change required for type 2 to type 1 epithelial differentiation.

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“…Integrins, composed of α- and β-subunits, mediate recognition and adhesion between cells or between cells and extracellular matrix. Several studies have shown that β1 integrins can regulate the proliferation, migration and invasion of tumor cells through different signal pathways [ 48 , 49 ]. FERMT2 has been shown to modulate β1 integrins activity in cancers.…”

Section: Discussionmentioning

confidence: 99%

Alzheimer’s risk factor FERMT2 promotes the progression of colorectal carcinoma via Wnt/β-catenin signaling pathway and contributes to the negative correlation between Alzheimer and cancer

et al. 2022

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Increasing evidence from epidemiological studies indicate that Alzheimer’s disease (AD) has a negative relationship with the incidence of cancers. Whether the Alzheimer’s genetic risk factor, named as fermitin family homolog-2 (FERMT2), plays a pivotal part in the progressive process of colorectal carcinoma (CRC) yet remains unclear. This study revealed that FERMT2 was upregulated in CRC tissues which predicted an unfavorable outcome of CRC using the PrognoScan web tool. FERMT2 was co-expressed with a variety of genes have been linked with CRC occurrence and implicated in the infiltration of immune cell in CRC tissues. Overexpressing FERMT2 promoted CRC progression with upregulation of Wnt/β-catenin signaling. Knockdown of FERMT2 suppressed the cell multiplication, colony formation rate, migration and invasion, along with the epithelial to mesenchymal transition (EMT) with downregulation Wnt/β-catenin proteins in cells of CRC, while overexpressing β-catenin reversed the inhibitory effects of silencing FERMT2 on the migration or invasion of CRC cells. Furthermore, Aβ1–42 treated HT22 cells induced downregulation of FERMT2 and inhibited the migration, invasion and EMT in co-cultured CT26 cells through Wnt/β-catenin signaling. Our results revealed that the downregulated FERMT2 gene during AD is prominently activated in CRC, which promotes its progression via Wnt/β-catenin pathway.

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Ligand-independent integrin β1 signaling supports lung adenocarcinoma development

Cited by 10 publications

References 51 publications

Alveolar repair following LPS-induced injury requires cell-ECM interactions

Alveolar repair following LPS-induced injury requires cell-ECM interactions

Alveolar Repair Following Lipopolysaccharide-induced Injury Requires Cell-Extracellular Matrix Interactions

Alzheimer’s risk factor FERMT2 promotes the progression of colorectal carcinoma via Wnt/β-catenin signaling pathway and contributes to the negative correlation between Alzheimer and cancer

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