Despite recent progress in identifying aberrant genetic and epigenetic alterations in esophageal squamous cell carcinoma (ESCC), the mechanism of ESCC initiation remain unknown. Using genetically engineered esophageal organoids (EOs), we identified the key genetic determinants that drive ESCC tumorigenesis. A single-cell transcriptomic analysis uncovered that Trp53, Cdkn2a, and Notch1 (PCN) triple knockout (KO) induces neoplastic features of ESCC by generating distinct cell lineage trajectories with multiple root cells and high cell plasticity. Although Trp53 and Notch1 (PN) double KO was sufficient to induce esophageal neoplasia and cellular heterogeneity, additional inactivation of Cdkn2a was indispensable for immune landscape remodeling for in vivo tumorigenesis. PCN KO generated immunosuppressive niche enriched with exhausted T cells and M2 macrophages via the CCL2-CCR2 axis in an autochthonous ESCC mouse model. Moreover, genetic or pharmacological blockade of the CCL2-CCR2 axis suppressed ESCC tumorigenesis. Comparative single-cell transcriptomic analyses classified ESCC patient tumors into three subgroups and identified a specific subset recapitulating PCN-type ESCC signatures, including the high expression of CCL2 and CD274/PD-L1. Our study unveils that loss of TP53, CDKN2A, and NOTCH1 induces esophageal neoplasia and immune evasion for ESCC initiation and proposes the CCL2 blockade as a viable approach to target a subset of ESCC.
Small cell lung carcinoma (SCLC) is a lethal neuroendocrine type of lung cancer with limited therapeutic options. Despite recent advances in cancer immunotherapy, the efficacy of immunotherapy is limited to a subset of patients with SCLC. However, the mechanisms responsible for refractoriness to immunotherapy remain elusive. CRACD (capping protein inhibiting regulator of actin dynamics; KIAA1211/CRAD) is frequently mutated and transcriptionally downregulated in SCLC. Here we show that Cracd knockout (KO) enhances transformation of preneoplastic neuroendocrine cells and significantly accelerates SCLC development initiated by loss of Rb1, Trp53, and Rbl2 in the lung epithelium of mice. Cracd KO increases tumor cell heterogeneity in SCLC tumors. Notably, the Cracd-deficient SCLC tumors display exclusion of CD8+ T cells, which coincides with epigenetic suppression of the MHC-I pathway. Single-cell transcriptomic analysis identifies SCLC patient tumors with concomitant inactivation of CRACD and impairment of tumor antigen presentation. These findings define CRACD as a novel tumor suppressor that regulates the proliferation and immune recognition of SCLC cells, providing new insight into the mechanisms by which SCLC evades immune surveillance.
Lysosomes play vital roles in the degradation and recycling of various macromolecules, protein secretion, energy metabolism, and cell signaling. Increasing evidence suggests that deregulated lysosomes contribute to tumorigenesis. However, the underlying mechanisms of lysosomal deregulation in cancer remain elusive. We herein identified transmembrane protein 9 (TMEM9) as a crucial protein that modulates lysosomal metabolism and lysosome-associated signaling.The TMEM9 gene is markedly amplified in breast cancer, correlated with its transcriptional upregulation. TMEM9 depletion suppressed the proliferation of TMEM9 high breast cancer cells.Consistently, Tmem9 knockout inhibited mammary tumorigenesis in the genetically engineered mouse model. Conversely, the ectopic expression of TMEM9 in TMEM9 low breast cancer cells promoted cell proliferation. The lysosome purification and proteomics approach showed that TMEM9 physically and functionally interacts with LAMTOR4, a subunit of the Ragulator complex, to hyperactivate mTOR signaling in breast cancer. Moreover, the pharmacological blockade of the TMEM9-v-ATPase axis, combined with mTOR inhibitors, exhibited the synergistic growth inhibition of breast cancer cells. Our results reveal the mechanism of TMEM9-v-ATPase-activated mTOR signaling and further indicate that the TMEM9-v-ATPase axis is a therapeutic target for overcoming mTOR inhibitor resistance in breast cancer.
Lysosomes play vital roles in the degradation and recycling of various macromolecules, protein secretion, energy metabolism, and cell signaling. Increasing evidence suggests that the deregulated lysosomes contribute to tumorigenesis and therapeutic resistance. However, its underlying mechanisms remain elusive. We herein identified transmembrane protein 9 (TMEM9) as a crucial protein modulating lysosomal metabolism and lysosome-associated signaling. The TMEM9 gene is markedly amplified in breast cancer, correlated with its transcriptional upregulation. TMEM9 depletion suppressed the proliferation of breast cancer cells highly expressing TMEM9. Consistently, Tmem9 knock-out inhibited mammary tumorigenesis in the genetically engineered mouse model. Conversely, the ectopic expression of TMEM9 in TMEM9 low breast cancer cells promoted cell proliferation. The lysosome purification and proteomics approach showed that TMEM9 physically and functionally interacts with LAMTOR4, a subunit of the Ragulator complex, to hyperactivate mTOR signaling in breast cancer. Moreover, the pharmacological blockade of the TMEM9-v-ATPase axis combined with mTOR inhibitors exhibited the synergistic growth inhibition of breast cancer cells. Our results reveal the mechanism of the TMEM9-v-ATPase-activated mTOR signaling and further propose the TMEM9-v-ATPase axis as a therapeutic target overcoming mTOR inhibitor resistance of breast cancer.
Despite the promising outcomes of immune checkpoint blockade (ICB), resistance to ICB presents a new challenge. Therefore, selecting patients for specific ICB applications is crucial for maximizing therapeutic efficacy. Herein we curated 69 human esophageal squamous cell cancer (ESCC) patients' tumor microenvironment (TME) single-cell transcriptomic datasets to subtype ESCC. Integrative analyses of the cellular network transcriptional signatures of T cells, myeloid cells, and fibroblasts define distinct ESCC subtypes characterized by T cell exhaustion, Interferon (IFN) a/b signaling, TIGIT enrichment, and specific marker genes. Furthermore, this approach classifies ESCC patients into ICB responders and non-responders, as validated by liquid biopsy single-cell transcriptomics. Our study stratifies ESCC patients based on TME transcriptional network, providing novel insights into tumor niche remodeling and predicting ICB responses in ESCC patients.
Gastric cancer (GC) is the third most common cancer and the second most common cause of cancer death in Asia. The highest incidence rates are observed in Eastern Asia. To date, the comprehensive mechanism of GC initiation remains elusive. Here, we discovered CRACD (Capping Protein Inhibiting Regulator of Actin Dynamics/CRAD/KIAA1211) as a tumor suppressor, frequently inactivated in GC. To determine the pathologic roles of CRACD, we employed Cracd knock-out (KO) mice and gastric organoids (GOs). Intriguingly, Cracd KO mice and GOs displayed hyperplastic gastric epithelium. Mechanistically, CRACD is essential for stabilizing the cadherin-catenin-actin (CCA) complex. The loss of CRACD leads to the release and nuclear translocation of β-catenin for Wnt target gene transactivation. Indeed, the genetic ablation of Cracd hyperactivated Wnt/β-catenin signaling with the disruption of the CCA complex. The genes encoding the Receptor Tyrosine Kinase (RTK)-RAS signaling pathway and the TP53 are genetically altered in 60% and 50% of gastric adenocarcinomas, respectively. To define the genetic interaction of Cracd loss with the RTK-RAS and TP53 signaling, we established genetically engineered GOs models carrying Trp53 deletion and KrasG12D activation in combination with Cracd KO (CKP) or Cracd wild type (KP). Compared to KP, CKP GOs exhibited neoplasia, higher mucin deposition, and increased carcinoma embryonic antigen (CEA) expression, pathologically related to the poor prognosis in GC patients. Meanwhile, loss of Cracd significantly accelerated the growth of CKP GOs with increased stemness. Furthermore, the CKP cell line derived from GOs exhibited relatively poor prognosis features of GC than KP cells in the xenograft models, represented by boosted tumor size and weight, poor differentiation, hyperplasia, increased CEA, and mucin secretion. Together, we identified CRACD as a tumor suppressor, of which inactivation contributes to GC initiation and progression, which may be translated into the development of a biomarker-guided regimen for CRACD mutations-associated GC patients. Citation Format: Gengyi Zou, Yuanjian Huang, Kyung Pil Ko, Shengzhe Zhang, Bong Jun Kim, Jie Zhang, Sohee Jun, Youn-Sang Jung, Biyun Zheng, Jae-Il Park. CRACD/CRAD, a tumor suppressor for gastric cancer development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 836.
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