Inhibition of the Stromal p38MAPK/MK2 Pathway Limits Breast Cancer Metastases and Chemotherapy-Induced Bone Loss

Murali, Bhavna; Ren, Qihao; Luo, Xianmin; Faget, Douglas V.; Wang, Chun; Johnson, Radia Marie; Gruosso, Tina; Flanagan, Kevin C.; Fu, Yujie; Leahy, K.; Alspach, Elise; Su, Xinming; Ross, Michael H.; Burnette, Brian L.; Weilbaecher, Katherine N.; Park, Morag; Mbalaviele, Gabriel; Monahan, Joseph B.; Stewart, Sheila A.

doi:10.1158/0008-5472.can-18-0234

Cited by 44 publications

(36 citation statements)

References 52 publications

(83 reference statements)

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“…Data in mice have shown that MK2 does contribute to tumor progression by promoting M2 macrophage polarization and tumor angiogenesis which in turns promotes tissue renovation that governs cell invasion and metastasis [31]. Furthermore, inhibition of the stromal p38MAPK/MK2 pathway was found to limit breast cancer metastases in mice [32]. These data from others along with our data showing the striking classification of metastasis status among gastric cancer patients by MK2 and its association with a wide range of cytokines suggests pathway blockade is promising for immunotherapy treatment [33].…”

Section: Discussionmentioning

confidence: 99%

The MK2 pathway is linked to G-CSF, cytokine production and metastasis in gastric cancer: a novel intercorrelation analysis approach

et al. 2020

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Background: Gastric cancer is associated with chronic inflammation, but there is still much to understand about the tumor microenvironment and the underlying tumor-promoting mechanisms. The Map kinase-activated protein kinase 2 (MK2) pathway is a regulator of inflammatory cytokine production that we have been studying in gastrointestinal cancers. Here, we set out to determine the significance of this gene in gastric cancer along with its downstream mediators and if there were differences in the primary tumors with and without metastasis. Methods: Human gastric cancer tissues with and without metastasis were examined for MK2 expression and cytokine profile in organ culture supernatants. Advanced statistical methods including a lower triangular correlation matrix, novel rooted correlation network, linear and logistic regression modeling along with Kruskal-Wallis testing with Sidak correction for multiple testing were applied to gain understanding of cytokines/chemokines linked to metastasis. Results: The MK2 pathway is strongly linked with metastasis and a panel of cytokines. Gene expression was able to classify gastric cancer metastasis 85.7% of the time. A significant association with a panel of cytokines was found, including G-CSF, GM-CSF, Mip-1β, IFN-α, MCP-1, IL-1β, IL-6, and TNF-α. Mip-1β was found to have the strongest association with MK2 and metastasis after Sidak correction for multiple testing. Conclusions: MK2 gene expression and a novel associated cytokine panel are linked to gastric cancer metastasis. G-CSF is the strongest cytokine to differentiate between metastasis and non-metastasis patients and had the lowest P value, while Mip-1β showed the strongest association with MK2 and metastasis after Sidak correction. MK2 and associated cytokines are potential biomarkers for gastric cancer metastasis. The novel intercorrelation analysis approach is a promising method for understanding the complex nature of cytokine/chemokine regulation and links to disease outcome.

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Section: Discussionmentioning

confidence: 99%

The MK2 pathway is linked to G-CSF, cytokine production and metastasis in gastric cancer: a novel intercorrelation analysis approach

et al. 2020

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“…We chose an ATI450 concentration of 1000 ppm for our preclinical mouse studies. This is lower than the maximum dose employed while still within the range of maximum MK2 pathway inhibition; furthermore, this concentration has been effective in previous publications [32,33].…”

Section: Ati450 Dosing Studiesmentioning

confidence: 78%

Substrate-based kinase activity inference identifies MK2 as driver of colitis

Strasser

Ghazi

Starchenko

et al. 2019

Integrative Biology

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Inflammatory bowel disease (IBD) is a chronic and debilitating disorder that has few treatment options due to a lack of comprehensive understanding of its molecular pathogenesis. We used multiplexed mass spectrometry to collect high-content information on protein phosphorylation in two different mouse models of IBD. Because the biological function of the vast majority of phosphorylation sites remains unknown, we developed Substrate-based Kinase Activity Inference (SKAI), a methodology to infer kinase activity from phosphoproteomic data. This approach draws upon prior knowledge of kinase-substrate interactions to construct custom lists of kinases and their respective substrate sites, termed kinase-substrate sets that employ prior knowledge across organisms. This expansion as much as triples the amount of prior knowledge available. We then used these sets within the Gene Set Enrichment Analysis framework to infer kinase activity based on increased or decreased phosphorylation of its substrates in a dataset. When applied to the phosphoproteomic datasets from the two mouse models, SKAI predicted largely non-overlapping kinase activation profiles. These results suggest that chronic inflammation may arise through activation of largely divergent signaling networks. However, the one kinase inferred to be activated in both mouse models was mitogen-activated protein kinase-activated protein kinase 2 (MAPKAPK2 or MK2), a serine/threonine kinase that functions downstream of p38 stress-activated mitogen-activated protein kinase. Treatment of mice with active colitis with ATI450, an orally bioavailable small molecule inhibitor of the MK2 pathway, reduced inflammatory signaling in the colon and alleviated the clinical and histological features of inflammation. These studies establish MK2 as a therapeutic target in IBD and identify ATI450 as a potential therapy for the disease.

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“…Senescent cells generated by genotoxic stress contributes to various toxicities, including tumor promotion and relapse, via secretion of various pro-inflammatory NASP factors [5][6][7] . Interestingly, exposure of MCF7 (breast cancer), A549 and HCC827 (lung cancer) cells to the CM of abemaciclib-induced senescent cells had a strongly reduced pro-proliferative effect in comparison to CM from doxorubicin-induced senescent cells (Extended data Fig.…”

Section: Abemaciclib Treatment Exerts Minimal Toxicitymentioning

confidence: 99%

“…Senescence induction acts as a potent tumor suppressive mechanism by restraining cancer cell proliferation and activating tumor immunosurveillance 4 . However, increasing evidence suggests that therapy-induced normal cells promote chronic inflammation and several shortand long-term adverse effects, including fatigue, myelosuppression, cardiomyopathy, bone loss, cancer progression and relapse, and that their genetic and pharmacological removal is sufficient to improve healthspan [5][6][7][8] . These senescence-associated detrimental effects are mainly mediated by pro-inflammatory SASP cytokines and chemokines, which are normally elevated in cancer patients suffering from a variety of adverse reactions to cancer therapies 9,10 .…”

Section: Introductionmentioning

confidence: 99%

Pharmacological CDK4/6 inhibition unravels a p53-induced secretory phenotype in senescent cells

Wang

Brandenburg

Hernandez‐Segura

et al. 2020

Preprint

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Cellular senescence is a state of stable growth arrest that acts as a tumor suppressive mechanism. Genotoxic agents exert their anti-cancer functions partly by inducing cancer cells into senescence. However, because of systemic administration and lack of specificity, treatment with genotoxic agents is associated with premature senescence of various non-cancerous cells. Therapy-induced normal senescent cells can have profound detrimental protumorigenic and pro-disease functions via activation of a pro-inflammatory secretory phenotype (SASP).Alternative to genotoxic agents, inhibitors of cyclin-dependent kinases 4/6 (CDK4/6i) have recently proven to be potent anti-cancer interventions able to activate a poorly characterized senescence-like state. Here, we demonstrate that establishment of CDK4/6i-induced stable growth arrest is dependent on p53 transcriptional activity. We show that in human cells, mouse tissues and plasma of metastatic breast cancer patients the CDK4/6i-induced senescent program engages only a partial SASP enriched in p53-associated genes (PASP) but without pro-inflammatory and detrimental NF-κB-dependent factors (NASP). Because of the lack of a NASP, CDK4/6i-induced p16 + senescent cells do not exert detrimental and pro-tumorigenic functions in culture and in vivo. Interestingly, short-term treatment of chemotherapy-induced senescent cells with CDK4/6i is sufficient to partially reduce an already established NASP and improve mouse healthspan via p53 activation and NF-κB repression. Our data suggest that short-and long-term treatment with CDK4/6i can modulate senescence-associated phenotypes and restrict the detrimental effects of senescent cells in cancer therapy.

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Inhibition of the Stromal p38MAPK/MK2 Pathway Limits Breast Cancer Metastases and Chemotherapy-Induced Bone Loss

Cited by 44 publications

References 52 publications

The MK2 pathway is linked to G-CSF, cytokine production and metastasis in gastric cancer: a novel intercorrelation analysis approach

The MK2 pathway is linked to G-CSF, cytokine production and metastasis in gastric cancer: a novel intercorrelation analysis approach

Substrate-based kinase activity inference identifies MK2 as driver of colitis

Pharmacological CDK4/6 inhibition unravels a p53-induced secretory phenotype in senescent cells

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