The loss of epithelial Smad4 drives immune evasion via CXCL1 while displaying vulnerability to combinatorial immunotherapy in gastric cancer

An, Hyeok-Won; Seok, Sang Hyeok; Kwon, Jong-Wan; Choudhury, Anahita Dev; Oh, Jeong-Seop; Voon, Dominic Chih-Cheng; Kim, Dae-Yong

doi:10.1016/j.celrep.2022.111878

Cited by 10 publications

(4 citation statements)

References 43 publications

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“…We hypothesize SMAD4 interacts with immune cells through some specific cytokines, such as chemokine (C-X-C motif) ligand 1 (CXCL1) and CCL15. An et al reckoned SMAD4-deficient gastric cancer inhibit dendritic cells(DC)differentiation and subsequently cytotoxic T cells infiltration via CXCL1 ( 40 ). Yamamoto et al viewed a lack of SMAD4 in colorectal cancer cells facilitates recruitment of neutrophils (CD15 + included) by releasing CCL15, which contributes to lung metastasis ( 41 ).…”

Section: Discussionmentioning

confidence: 99%

The effect of SMAD4 on the prognosis and immune response in hypopharyngeal carcinoma

Song

Ding

et al. 2023

Front. Med.

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ObjectivesIn malignant tumors, elevated infiltration of intratumoral CD8+ cytotoxic T cells predicts a beneficial prognosis, whereas high levels of CD15+ neutrophils in peritumor tissues indicate poor prognosis. It is unclear how SMAD4, which promotes favorable clinical outcomes and antitumor immunoregulation, along with CD8+ cytotoxic T cells and CD15+ neutrophils exert an influence on hypopharyngeal carcinoma (HPC).Materials and methodsSpecimens were collected from 97 patients with HPC. Immunohistological analyses of SMAD4, CD8+ cytotoxic T cell and CD15+ neutrophil expression were performed. SMAD4 nuclear intensity was measured, meanwhile, CD8+ cytotoxic T cells and CD15+ neutrophils were counted under a microscope. The prognostic role of SMAD4 was determined using the log-rank test and univariate and multivariate analyses. The relationship among SMAD4, CD8+ cytotoxic T cells, and CD15+ neutrophils was estimated by Mann–Whitney U test.ResultsHigh levels of SMAD4 were associated with favorable overall survival (OS) and disease-free survival (DFS) in HPC. Multivariate analysis suggested that SMAD4 is an independent predictor of OS and DFS. A high density of intratumoral CD8+ cytotoxic T cells and low accumulation of CD15+ neutrophils in the peritumor area were associated with longer OS and DFS. Furthermore, SMAD4 was linked to the levels of intratumoral CD8+ cytotoxic T cells and peritumoral CD15+ neutrophils. Patients with high SMAD4/high intratumoral CD8+ cytotoxic T cells or high SMAD4/low peritumoral CD15+ neutrophils showed the best prognosis.ConclusionSMAD4, CD8+ cytotoxic T cell level, and CD15+ neutrophil level have prognostic value in HPC. SMAD4 is a promising prognostic marker reflecting immune response in HPC.

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Section: Discussionmentioning

confidence: 99%

The effect of SMAD4 on the prognosis and immune response in hypopharyngeal carcinoma

Song

Ding

et al. 2023

Front. Med.

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“…Mouse stomach organoids were primarily cultured directly from mouse stomach tissues, as described previously [ 13 , 20 ]. To generate Trp53 KO mouse stomach organoids (P organoid), the gastric epithelium of Cre-dependent Cas9 + - Trp53 fl / fl mice was used.…”

Section: Methodsmentioning

confidence: 99%

“…Additionally, the Cdh1 F/+ ; Trp53 F/F ; Smad4 F/F (ChetPS) GC mouse model represents a unique preclinical model that recapitulates the malignant progression of human GC [ 8 , 11 , 12 ]. The ChetPS GC mouse model has provided insights into GC metastasis and therapeutic vulnerability based on genetic features [ 9 , 13 ]. Further comprehensive gene screening approaches to identify functional drivers of metastasis using such preclinical models may offer valuable clues for rationalized and personalized treatment options for metastatic GC.…”

Section: Introductionmentioning

confidence: 99%

Combined inhibition of Bcl-2 family members and YAP induces synthetic lethality in metastatic gastric cancer with RASA1 and NF2 deficiency

Kwon,

Oh,

Seok

et al. 2023

Mol Cancer

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Background Targetable molecular drivers of gastric cancer (GC) metastasis remain largely unidentified, leading to limited targeted therapy options for advanced GC. We aimed to identify molecular drivers for metastasis and devise corresponding therapeutic strategies. Methods We performed an unbiased in vivo genome-wide CRISPR/Cas9 knockout (KO) screening in peritoneal dissemination using genetically engineered GC mouse models. Candidate genes were validated through in vivo transplantation assays using KO cells. We analyzed target expression patterns in GC clinical samples using immunohistochemistry. The functional contributions of target genes were studied through knockdown, KO, and overexpression approaches in tumorsphere and organoid assays. Small chemical inhibitors against Bcl-2 members and YAP were tested in vitro and in vivo. Results We identified Nf2 and Rasa1 as metastasis-suppressing genes through the screening. Clinically, RASA1 mutations along with low NF2 expression define a distinct molecular subtype of metastatic GC exhibiting aggressive traits. NF2 and RASA1 deficiency increased in vivo metastasis and in vitro tumorsphere formation by synergistically amplifying Wnt and YAP signaling in cancer stem cells (CSCs). NF2 deficiency enhanced Bcl-2-mediated Wnt signaling, conferring resistance to YAP inhibition in CSCs. This resistance was counteracted via synthetic lethality achieved by simultaneous inhibition of YAP and Bcl-2. RASA1 deficiency amplified the Wnt pathway via Bcl-xL, contributing to cancer stemness. RASA1 mutation created vulnerability to Bcl-xL inhibition, but the additional NF2 deletion conferred resistance to Bcl-xL inhibition due to YAP activation. The combined inhibition of Bcl-xL and YAP synergistically suppressed cancer stemness and in vivo metastasis in RASA1 and NF2 co-deficiency. Conclusion Our research unveils the intricate interplay between YAP and Bcl-2 family members, which can lead to synthetic lethality, offering a potential strategy to overcome drug resistance. Importantly, our findings support a personalized medicine approach where combined therapy targeting YAP and Bcl-2, tailored to NF2 and RASA1 status, could effectively manage metastatic GC.

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“…In addition, SMAD4 deletion increased programmed cell death ligand-1 (PD-L1) and decreased 4-1BBL expression, indicating altered immunogenicity. Combined immune checkpoint blockade (ICB) with anti-PD-L1 and anti-CTLA-4 or agonistic anti-4-1BB antibodies effectively treats ICB monotherapyresistant SMAD4-deficient allografts, providing a rational basis for an ICB strategy to treat advanced SMAD4-deficient GC [38].…”

Section: Gastric Cancermentioning

confidence: 99%

SMAD Proteins in TGF-β Signalling Pathway in Cancer: Regulatory Mechanisms and Clinical Applications

Wang,

Xiong,

et al. 2023

Diagnostics

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Suppressor of mother against decapentaplegic (SMAD) family proteins are central to one of the most versatile cytokine signalling pathways in metazoan biology, the transforming growth factor-β (TGF-β) pathway. The TGF-β pathway is widely known for its dual role in cancer progression as both an inhibitor of tumour cell growth and an inducer of tumour metastasis. This is mainly mediated through SMAD proteins and their cofactors or regulators. SMAD proteins act as transcription factors, regulating the transcription of a wide range of genes, and their rich post-translational modifications are influenced by a variety of regulators and cofactors. The complex role, mechanisms, and important functions of SMAD proteins in tumours are the hot topics in current oncology research. In this paper, we summarize the recent progress on the effects and mechanisms of SMAD proteins on tumour development, diagnosis, treatment and prognosis, and provide clues for subsequent research on SMAD proteins in tumours.

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The loss of epithelial Smad4 drives immune evasion via CXCL1 while displaying vulnerability to combinatorial immunotherapy in gastric cancer

Cited by 10 publications

References 43 publications

The effect of SMAD4 on the prognosis and immune response in hypopharyngeal carcinoma

The effect of SMAD4 on the prognosis and immune response in hypopharyngeal carcinoma

Combined inhibition of Bcl-2 family members and YAP induces synthetic lethality in metastatic gastric cancer with RASA1 and NF2 deficiency

SMAD Proteins in TGF-β Signalling Pathway in Cancer: Regulatory Mechanisms and Clinical Applications

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