The liver exhibits the highest recovery rate from acute injuries. However, in chronic liver disease, the long-term loss of hepatocytes often leads to adverse consequences such as fibrosis, cirrhosis, and liver cancer. The Wnt signaling plays a pivotal role in both liver regeneration and tumorigenesis. Therefore, manipulating the Wnt signaling has become an attractive approach to treating liver disease, including cancer. Nonetheless, given the crucial roles of Wnt signaling in physiological processes, blocking Wnt signaling can also cause several adverse effects. Recent studies have identified cancer-specific regulators of Wnt signaling, which would overcome the limitation of Wnt signaling target approaches. In this review, we discussed the role of Wnt signaling in liver regeneration, precancerous lesion, and liver cancer. Furthermore, we summarized the basic and clinical approaches of Wnt signaling blockade and proposed the therapeutic prospects of cancer-specific Wnt signaling blockade for liver cancer treatment.

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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.

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.

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.