Xiaobing Wang

Background: Pancreatic cancer development requires oncogenic KRAS plus additional genetic hits, yet these cooperating events remain poorly defined. Starting from a germline SKIL A512T mutation discovered in an infant with IPMN, we explored the synergistic role of SKIL and KRAS in tumorigenesis. Methods: HEK293T cells with engineered SKIL A512T and/or KRAS G12V mutations were analyzed for proliferation, tumorigenicity, and signaling. Transcriptomics, ubiquitination assays, and protein interaction studies (Co-IP, immunofluorescence) delineated the mechanism. Results: SKIL normally protects Smad4 by binding its MH2 domain; SKIL loss exposes this domain to ubiquitination, but degradation occurs only when KRAS mutation upregulates the E3 ligase SMURF2. Clinically, a significant positive correlation was observed between SKIL and Smad4 protein expression in KRAS -mutant IPMN tissues. Conclusion: We identify a novel synergy between SKIL loss and KRAS activation that drives pancreatic tumorigenesis through targeted Smad4 degradation. This study aids in identifying high-risk populations for pancreatic cancer, specifically those harboring KRAS mutations.

Background: Gastric cancer (GC) is a prevalent malignancy in China, posing significant health challenges. The persistently high tumor incidence and the rising number of tumor survivors may elevate the risk of multiple primary malignancies (MPMs) in GC patients. Methods: We conducted a retrospective study involving 11,045 patients diagnosed with gastric adenocarcinoma at National Cancer Center of China between 2010 and 2017. A 6‐month interval distinguished synchronous MPMs (SMPMs) from metachronous MPMs (MMPMs). Results: Of all GC patients, 443 (4.01%) had MPM, with 75.85% being males and an average age of 60 at initial diagnosis. Among the MPM cases, 415 (93.68%) had two primary cancers (53.98% synchronous and 46.02% metachronous), 27 (6.09%) had three, and 1 (0.23%) had four, totaling 472 extra gastric cancer sites. Esophageal, colorectal, and lung cancers were the most prevalent concomitant malignancies, with esophageal cancer more frequent in synchronous cases and breast cancer (observed only in females) more frequent in metachronous cases (both p < 0.001). In patients with two primary cancers, the SMPM subset included more males ( p < 0.001), with higher rates of smoking ( p = 0.012), alcohol consumption ( p < 0.001), and higher T stage at first diagnosis ( p < 0.001). The MMPM subset included more females ( p < 0.001), was younger at first diagnosis ( p < 0.001), and more frequently underwent surgery after first diagnosis ( p < 0.001). Conclusions: MPM occurring in patients with GC predominantly involve the esophagus, colorectum, and lung. Elderly male patients with smoking or alcohol use represent a higher‐risk group and warrant vigilant surveillance. This study provides a clinical and epidemiologic basis for future research on MPM in GC.

Recent studies have highlighted the pivotal role of the cGAS‐STING pathway in cancer immunotherapy. However, clinical trials with cGAS‐STING pathway agonists have faced setbacks thanks to their short biological half‐life, lack of tumor specificity, and potential to promote tumor immune evasion. To address these challenges, a novel exosome‐based drug delivery platform, termed cmExo ^aCD11b is developed, designed to precisely target and reprogram the tumor microenvironment (TME) in situ for pancreatic cancer immunotherapy. cmExo ^aCD11b is engineered to encapsulate high copy numbers of IL‐12 mRNA and 2′3’‐cGAMP (cGAMP) and is functionalized with CD11b antibodies for targeted delivery to macrophages. Notably, cmExo ^aCD11b facilitated the repolarization of M2 macrophages to M1 phenotype, thereby reprogramming the TME and enhancing the secretion of pro‐inflammatory cytokines. This immunomodulatory effect reversed the immunosuppressive milieu of the TME and significantly inhibited tumor progression. More importantly, cmExo ^aCD11b exhibited robust therapeutic efficacy in both murine pancreatic cancer and patient‐derived xenograft models. These results suggest that cmExo ^aCD11b represents a promising approach for overcoming immunosuppression in pancreatic cancer, paving the way for its potential application in cancer immunotherapy.

Background: Pancreatic adenocarcinoma (PAAD) represents a highly fatal form of cancer. The 5‐year survival rate for patients with this disease is only around 10%. A significant hurdle in its management is the absence of characteristic early‐stage symptoms. As a result, a large majority of pancreatic cancer patients are diagnosed when the disease has reached an advanced stage or has metastasized. Consequently, taking measures to suppress the occurrence of metastasis in pancreatic cancer can bring about a substantial improvement in patients' survival rates and overall prognosis. SKIL, known to promote cancer progression, is implicated in cell proliferation, epithelial–mesenchymal transition (EMT), and metastasis, but its specific function in pancreatic cancer remains unclear.Methods: We investigated the effects of SKIL on the proliferation, apoptosis, and metastasis of pancreatic cancer cells. Through ChIP‐seq, we identified the SKIL downstream target gene and further explored the mechanism by which SKIL regulates the metastasis of pancreatic cancer cells through functional experiments and Western blot.Results: A high level of SKIL expression is associated with an unfavorable prognosis in PAAD; it promotes cell migration and EMT. Through ChIP‐seq analysis, we identified that SKIL inhibits TSPYL2, a nuclear protein regulating the TGF‐β pathway by binding to the TGFB1 promoter. Further studies carried out by us confirmed that SKIL modulates the TGF‐β pathway via TSPYL2, facilitating EMT and metastasis in pancreatic cancer cells, independent of Smad4.Conclusions: These findings reveal a novel regulatory mechanism involving SKIL, TSPYL2, and the TGF‐β pathway, offering new therapeutic targets for PAAD.

Colorectal neuroendocrine tumors with liver metastases (CRNELM) are associated with a poorer prognosis compared to their nonmetastatic counterparts. A comprehensive understanding of the tumor microenvironment (TME) heterogeneity between primary lesions (PL) and liver metastases (LM) could provide crucial insights for enhancing clinical management strategies for these patients. We utilized single-cell RNA sequencing to analyze fresh tissue samples from CRNELM patients, aiming to elucidate the variations in TME between PL and LM. Complementary multidimensional validation was achieved through spatial transcriptomics, bulk RNA sequencing, and multiplex immunohistochemistry/immunofluorescence. Our single-cell RNA sequencing analysis revealed that LM harboured a higher proportion of CD8 + T cells, CD4 + T cells, NK cells, NKT cells, and B cells exhibiting a stress-like phenotype compared to PL. RGS5 + pericytes may play a role in the stress-like phenotype observed in immune cells within LM. MCs in PL (PL_MCs) and LM (LM_MCs) exhibit distinct activation of tumor-associated signaling pathways. Notably, COLEC11 + matrix cancer-associated fibroblasts (COLEC11_mCAFs) were found to be significantly associated with LM_MCs. Cell communication analysis unveiled potential targetable receptor-ligand interactions between COLEC11_mCAFs and LM_MCs. Multidimensional validation confirmed the prominence of the characteristic stress-like phenotypes, including HSPA6_CD8_Tstr, HSPA6_NK, and COLEC11_mCAFs in LM. Moreover, a higher abundance of COLEC11_mCAFs correlated with poorer survival rates in the neuroendocrine tumor patient cohort. Overall, our study provides the first single-cell analysis of the cellular and molecular differences between PL and LM in CRNELM patients. We identified distinct cell subsets and receptor-ligand interactions that may drive TME discrepancies and support metastatic tumor growth. These insights highlight potential therapeutic targets and inform strategies for better managing CRNELM patients.