Real-time sensing of MAPK signaling in medulloblastoma cells reveals cellular evasion mechanism counteracting dasatinib blockade of ERK activation during invasion

Schönholzer, Marc Thomas; Migliavacca, Jessica; Álvarez, Elena; Kumar, Karthiga Santhana; Neve, Anuja; Gries, Alexandre; Ma, Min; Grotzer, Michael A.; Baumgärtner, Martin

doi:10.1016/j.neo.2020.07.006

Cited by 15 publications

(15 citation statements)

References 46 publications

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“…PDMs were cultured in 96-well plates together with autologous TILs at an effector: target cell ratio of 4:1 with the CellTox™ Green Cytotoxicity Assay reagent (Promega, Madison, WI, USA) [ 42 ]. Treatments included anti-CSF1R antibody [ 21 ], anti-PD1 antibody (Absource Diagnostics GmbH, Munich, Germany), and the respective human IgG4 isotype control (Invivogen, San Diego, CA, USA) at indicated concentrations and time points (each measured in triplicates).…”

Section: Methodsmentioning

confidence: 99%

Targeting CSF1R Alone or in Combination with PD1 in Experimental Glioma

Przystal

Becker

Canjuga

et al. 2021

Cancers

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Glioblastoma is an aggressive primary tumor of the central nervous system. Targeting the immunosuppressive glioblastoma-associated microenvironment is an interesting therapeutic approach. Tumor-associated macrophages represent an abundant population of tumor-infiltrating host cells with tumor-promoting features. The colony stimulating factor-1/ colony stimulating factor-1 receptor (CSF-1/CSF1R) axis plays an important role for macrophage differentiation and survival. We thus aimed at investigating the antiglioma activity of CSF1R inhibition alone or in combination with blockade of programmed death (PD) 1. We investigated combination treatments of anti-CSF1R alone or in combination with anti-PD1 antibodies in an orthotopic syngeneic glioma mouse model, evaluated post-treatment effects and assessed treatment-induced cytotoxicity in a coculture model of patient-derived microtumors (PDM) and autologous tumor-infiltrating lymphocytes (TILs) ex vivo. Anti-CSF1R monotherapy increased the latency until the onset of neurological symptoms. Combinations of anti-CSF1R and anti-PD1 antibodies led to longterm survivors in vivo. Furthermore, we observed treatment-induced cytotoxicity of combined anti-CSF1R and anti-PD1 treatment in the PDM/TILs cocultures ex vivo. Our results identify CSF1R as a promising therapeutic target for glioblastoma, potentially in combination with PD1 inhibition.

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Section: Methodsmentioning

confidence: 99%

Targeting CSF1R Alone or in Combination with PD1 in Experimental Glioma

Przystal

Becker

Canjuga

et al. 2021

Cancers

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“…PyMT-GFP or 231-GFP spheroids were generated with or without collagen IV and treated with 10nM dasatinib or 1μM defactinib. These doses were chosen to detect anti-invasive effects while having minimal effect on cell proliferation or viability as described previously (46)(47)(48). In PyMT-GFP cells, inhibition of FAK, but not Src, reduced spheroid growth in collagen I, in the absence of collagen IV.…”

Section: Knockdown Of Integrin α1/α2 and Inhibition Of Src Or Fak Red...mentioning

confidence: 99%

Chemotherapy-Induced Collagen IV Drives Cancer Cell Motility through Activation of Src and Focal Adhesion Kinase

et al. 2022

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Triple-negative breast cancer (TNBC) is the most aggressive and deadly subtype of breast cancer, accounting for 30,000 cases annually in the US. While there are several clinical trials ongoing to identify new agents to treat TNBC, the majority of TNBC patients are treated with anthracycline- or taxane-based chemotherapies in the neoadjuvant setting, followed by surgical resection and adjuvant chemotherapy. While many patients respond well to this approach, as many as 25% will suffer local or metastatic recurrence within five years. Understanding the mechanisms that drive recurrence after chemotherapy treatment is critical to improving survival for patients with TNBC. It is well-established that the extracellular matrix, which provides structure and support to tissues, is a major driver of tumor growth, local invasion and dissemination of cancer cells to distant metastatic sites. In the present study, we show that decellularized extracellular matrix (dECM) obtained from chemotherapy-treated mice increases motility of treatment-naïve breast cancer cells compared to vehicle-treated dECM. Tandem-mass-tag proteomics revealed that anthracycline- and taxane-based chemotherapies induce drug-specific changes in tumor ECM composition. The basement membrane protein collagen IV was significantly upregulated in the ECM of chemotherapy-treated mice and patients treated with neoadjuvant chemotherapy. Collagen IV drove invasion via activation of Src and focal adhesion kinase signaling downstream of integrin α1 and α2, and inhibition of collagen IV-driven signaling decreased motility in chemotherapy-treated dECM. These studies provide a novel mechanism by which chemotherapy may induce metastasis via its effects on ECM composition.

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“…STRIP1 depletion has been associated with a contractile motility mode, supporting migration in confined, stiff spaces[64]. Rounded, blebbing motility may contribute to brain invasion, albeit at lower efficacy, and we previously observed a similar phenomenon in cells treated with the SRC-BCR/ABL inhibitor dasatinib, which represses mesenchymal migration[65].…”

Section: Discussionmentioning

confidence: 77%

Striatin 3 and MAP4K4 cooperate towards oncogenic growth and tissue invasion in medulloblastoma

Migliavacca

Züllig

Capdeville

et al. 2021

Preprint

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Proliferation and motility are mutually exclusive biological processes associated with cancer that depend on precise control of upstream signaling pathways with overlapping functionalities. We find that STRN3 and STRN4 scaffold subunits of the STRIPAK complex interact with MAP4K4 for pathway regulation in medulloblastoma. Disruption of the MAP4K4-STRIPAK complex impairs growth factor-induced migration and tissue invasion and stalls YAP/TAZ target gene expression and oncogenic growth. The migration promoting functions of the MAP4K4-STRIPAK complex involve the activation of novel PKCs and the phosphorylation of the membrane targeting S157 residue of VASP through MAP4K4. The anti-proliferative effect of complex disruption is associated with reduced YAP/TAZ target gene expression and results in repressed tumor growth in the brain tissue. This dichotomous functionality of the STRIPAK complex in migration and proliferation control acts through MAP4K4 regulation in tumor cells and provides relevant mechanistic insights into novel tumorigenic functions of the STRIPAK complex in medulloblastoma.

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Real-time sensing of MAPK signaling in medulloblastoma cells reveals cellular evasion mechanism counteracting dasatinib blockade of ERK activation during invasion

Cited by 15 publications

References 46 publications

Targeting CSF1R Alone or in Combination with PD1 in Experimental Glioma

Targeting CSF1R Alone or in Combination with PD1 in Experimental Glioma

Chemotherapy-Induced Collagen IV Drives Cancer Cell Motility through Activation of Src and Focal Adhesion Kinase

Striatin 3 and MAP4K4 cooperate towards oncogenic growth and tissue invasion in medulloblastoma

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