Cross-talk between GLI transcription factors and FOXC1 promotes T-cell acute lymphoblastic leukemia dissemination

Tosello, Valeria; Bongiovanni, Deborah; Liu, Jingjing; Pan, Qingfei; Yan, Koon kiu; Saccomani, Valentina; Trimpont, Maaike Van; Pizzi, Marco; Mazzoni, Martina; Tos, Angelo Paolo Dei; Amadori, Alberto; Zanovello, Paola; Vlierberghe, Pieter Van; Yu, Jiyang; Piovan, Erich

doi:10.1038/s41375-020-0999-2

Cited by 11 publications

(7 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The relevance of cortactin overexpression in solid tumors and its association with metastasis and worse prognosis has been well studied [16,19,32]. Of note, expression of cortactin has also been found in different leukemias, such as B-cell chronic lymphocytic leukemia, B-ALL [20,24] and T-ALL [14,31,43]. In agreement, we report here increased levels of cortactin in the T-ALL cell lines Jurkat and Molt-3 when compared to healthy T cells.…”

Section: Discussionsupporting

confidence: 87%

“…In agreement, we report here increased levels of cortactin in the T-ALL cell lines Jurkat and Molt-3 when compared to healthy T cells. So far, our knowledge of the relevance of cortactin in T-ALL is limited to the regulation of surface CXCR4 levels and CXCR4-mediated migration [14,31]. However, we did not detect reduced CXCR4 surface levels due to loss of cortactin in our T cell models.…”

Section: Discussioncontrasting

confidence: 55%

“…Defective migration of Cttn −/− T cells depends on the Arp2/3 complex Since cortactin has been associated with CXCR4 regulation [14,31], we wanted to know whether cortactin de ciency affects migration. To this end, we performed chemotaxis assays using transwell lters and CXCL12, the CXCR4 ligand, as chemoattractant.…”

Section: Resultsmentioning

confidence: 99%

See 2 more Smart Citations

T cell activation, immune synapse formation, and organ infiltration by leukemic T cells require cortactin

Castellanos-Martínez¹,

León-Vega²,

Guerrero‐Fonseca³

et al. 2022

Preprint

View full text Add to dashboard Cite

T cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy that is still fatal in many cases. T cell blasts are characterized by hyperactivation and strong proliferative and migratory capacities. The chemokine receptor CXCR4 is involved in mediating malignant T cell properties and cortactin has been shown to control CXCR4 surface localization in T-ALL cells. We have previously shown that cortactin overexpression is correlated with organ infiltration and relapse in B-ALL. However, the role of cortactin in T cell biology and T-ALL remains elusive. Here, we analyzed the functional relevance of cortactin for T cell activation and migration and the implications for T-ALL development. We found that cortactin is upregulated in response to TCR engagement and recruited to the immune synapse in normal T cells. Loss of cortactin caused reduced IL-2 production and proliferation. Cortactin-depleted T cells showed defects in immune synapse formation and migrated less due to impaired actin polymerization in response to TCR and CXCR4 stimulation. Leukemic T cells expressed much higher levels of cortactin compared to normal T cells that correlated with greater migratory capacity. Xenotransplantation assays in NSG mice revealed that cortactin-depleted human leukemic T cells colonized the bone marrow significantly less and failed to infiltrate the central nervous system suggesting that cortactin overexpression drives organ infiltration, which is a major complication of T-ALL relapse. Thus, cortactin could serve as a potential therapeutic target for T-ALL and other pathologies involving aberrant T cell responses.

show abstract

Section: Discussionsupporting

confidence: 87%

Section: Discussioncontrasting

confidence: 55%

See 1 more Smart Citation

T cell activation, immune synapse formation, and organ infiltration by leukemic T cells require cortactin

Castellanos-Martínez¹,

León-Vega²,

Guerrero‐Fonseca³

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…HH signaling is a stemness pathway crucial during embryonic development but largely inactive in adult life except during tissue repair [7]. However, aberrant activation of HH signaling has been identified in a variety of cancer types [34] (including T-ALL [21,22,35]), driving proliferation, self-renewal, and tumorigenesis. Extensive crosstalk exists between the HH pathway and other oncogenic or stemness signaling pathways, such as RAS/RAF/MERK/ERK, PI3K/AKT, mTOR/S6K1, EGFR, and NOTCH1 [36].…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, AMPK has been reported to directly phosphorylate and destabilize GLI1 protein, inhibiting GLI1 nuclear localization resulting in the suppression of HH signaling [19,20]. Although recent studies have shown that HH signaling is active in a subgroup of T-ALL cases and may play a role in T-ALL progression, only modest therapeutic activity has been found using HH inhibitors (iHHs) in monotherapy [21,22]. Thus, identification of signaling pathways that alter sensitivity to iHHs under metabolic conditions encountered within the tumor microenvironment is imperative for increasing their therapeutic efficacy [23].…”

Section: Introductionmentioning

confidence: 99%

Responsiveness to Hedgehog Pathway Inhibitors in T-Cell Acute Lymphoblastic Leukemia Cells Is Highly Dependent on 5′AMP-Activated Kinase Inactivation

Tosello

Bongiovanni

Martino

et al. 2021

IJMS

Self Cite

View full text Add to dashboard Cite

Numerous studies have shown that hedgehog inhibitors (iHHs) only partially block the growth of tumor cells, especially in vivo. Leukemia often expands in a nutrient-depleted environment (bone marrow and thymus). In order to identify putative signaling pathways implicated in the adaptive response to metabolically adverse conditions, we executed quantitative phospho-proteomics in T-cell acute lymphoblastic leukemia (T-ALL) cells subjected to nutrient-depleted conditions (serum starvation). We found important modulations of peptides phosphorylated by critical signaling pathways including casein kinase, mammalian target of rapamycin, and 5′AMP-activated kinase (AMPK). Surprisingly, in T-ALL cells, AMPK signaling was the most consistently downregulated pathway under serum-depleted conditions, and this coincided with increased GLI1 expression and sensitivity to iHHs, especially the GLI1/2 inhibitor GANT-61. Increased sensitivity to GANT-61 was also found following genetic inactivation of the catalytic subunit of AMPK (AMPKα1) or pharmacological inhibition of AMPK by Compound C. Additionally, patient-derived xenografts showing high GLI1 expression lacked activated AMPK, suggesting an important role for this signaling pathway in regulating GLI1 protein levels. Further, joint targeting of HH and AMPK signaling pathways in T-ALL cells by GANT-61 and Compound C significantly increased the therapeutic response. Our results suggest that metabolic adaptation that occurs under nutrient starvation in T-ALL cells increases responsiveness to HH pathway inhibitors through an AMPK-dependent mechanism and that joint therapeutic targeting of AMPK signaling and HH signaling could represent a valid therapeutic strategy in rapidly expanding tumors where nutrient availability becomes limiting.

show abstract

ABT-737 suppresses aberrant Hedgehog pathway and overcomes resistance to smoothened antagonists by blocking Gli

et al. 2022

View full text Add to dashboard Cite

Cross-talk between GLI transcription factors and FOXC1 promotes T-cell acute lymphoblastic leukemia dissemination

Cited by 11 publications

References 33 publications

T cell activation, immune synapse formation, and organ infiltration by leukemic T cells require cortactin

T cell activation, immune synapse formation, and organ infiltration by leukemic T cells require cortactin

Responsiveness to Hedgehog Pathway Inhibitors in T-Cell Acute Lymphoblastic Leukemia Cells Is Highly Dependent on 5′AMP-Activated Kinase Inactivation

ABT-737 suppresses aberrant Hedgehog pathway and overcomes resistance to smoothened antagonists by blocking Gli

Contact Info

Product

Resources

About