Stem cells play a pivotal role in the malignant behavior of gastric cancer (GC), complicating its treatment and prognosis. However, the regulatory mechanisms of GC stem cells (GCSCs) remain poorly understood. DAZ-associated protein 1 (DAZAP1), a splicing regulator linked to various malignancies, has an unclear role in GC. This study investigated DAZAP1's impact on GC stemness and its mechanisms. DAZAP1 promoted tumor progression in GCSCs, as shown by sphere formation assays and stemness marker analysis. Functional enrichment analysis suggested that DAZAP1 enhanced tumor stemness by promoting oxidative phosphorylation (OXPHOS), which was validated through Seahorse assays and measurements of mitochondrial potential. Transmission electron microscopy and immunofluorescence analyses demonstrated that DAZAP1 promoted mitophagy. RNA immunoprecipitation and PCR analysis revealed that DAZAP1 regulated the splicing and expression of the mitophagy-related gene ULK1 through nonsense-mediated mRNA decay. Rescue experiments showed that overexpression of ULK1 reversed the suppression of GC stemness and OXPHOS levels induced by DAZAP1 silencing. Our findings indicate that DAZAP1 reduces ULK1 decay, thereby activating mitophagy and enhancing OXPHOS to fulfill the metabolic demands of cancer stem cells. These findings highlight the therapeutic potential of DAZAP1 as a target for treating GC.

Osteopontin (OPN) is a multifunctional secretory protein which can be expressed and secreted by a variety of tumor cells and immune cells. Tumor microenvironment remodeling provides favorable conditions for tumor progression, immune escape and therapy resistance. As a bridge molecule in crosstalk between tumor cells and tumor microenvironment, OPN can not only come from tumor cells to regulate the functions of various immune cells, promoting the formation of immunosuppressive environment, but also can be secreted by immune cells to act on tumor cells, leading to tumor progression, thus constructing a positive feedback regulatory network. Here, we summarize the molecular structure, source and receptor of OPN, and clarify the mechanism of OPN on tumor-associated macrophages, dendritic cells, myeloid-derived suppressor cells, tumor progression and therapy resistance to comprehensively understand the great potential of OPN as a tumor biomarker and therapeutic target.

Therapeutic target identification is challenging in drug discovery, particularly for rare and orphan diseases. Here, we propose a disease signature, TRESOR, which characterizes the functional mechanisms of each disease through genome-wide association study (GWAS) and transcriptome-wide association study (TWAS) data, and develop machine learning methods for predicting inhibitory and activatory therapeutic targets for various diseases from target perturbation signatures (i.e., gene knockdown and overexpression). TRESOR enables highly accurate identification of target candidate proteins that counteract disease-specific transcriptome patterns, and the Bayesian optimization with omics-based disease similarities achieves the performance enhancement for diseases with few or no known targets. We make comprehensive predictions for 284 diseases with 4345 inhibitory target candidates and 151 diseases with 4040 activatory target candidates, and elaborate the promising targets using several independent cohorts. The methods are expected to be useful for understanding disease-disease relationships and identifying therapeutic targets for rare and orphan diseases.

Cancer chemoresistance presents a challenge in oncology, often leading to treatment failure and disease progression. CD44, a multifunctional cell surface glycoprotein, has garnered attention for its involvement in various aspects of cancer biology. Through alternative splicing, CD44 can form isoforms with the inclusion of only standard exons, typical for normal tissue, or with the addition of variant exons, frequently expressed in cancer tissue and associated with chemoresistance. The functions of CD44 involved in regulation of cancer signaling pathways are being actively studied, and the significance of specific variant exons in modulating cell death pathways, central to the response of cancer cells to chemotherapy, begins to become apparent. This review provides a comprehensive analysis of the association of CD44 variant exons/total CD44 with clinical outcomes of patients undergoing chemotherapy. The role of CD44 variant exons v6, v9 and others with a significant effect on patient chemotherapy outcomes by means of key cellular death pathways such as apoptosis, ferroptosis and autophagy modulation is further identified, and their impact on drug resistance is highlighted. An overview of clinical trials aimed at targeting variant exon-containing isoforms is provided, and possible directions for further development of CD44-targeted therapeutic strategies are discussed.

The relapse of tongue cancer (TC) after chemotherapy is caused by minimal residual disease (MRD), which is a few remaining cancer cells after chemotherapy. To understand the mechanism of MRD in TC, we created a library of TC organoids (TCOs) from 28 untreated TC patients at diverse ages and cancer stages. These TCOs reproduced the primary TC tissues both in vitro and in a xenograft model, and several TCO lines survived after cisplatin treatment (chemo-resistant TCOs). Of note, the chemo-resistant TCOs showed "heritable" embryonic diapause-like features before treatment and activation of the autophagy and cholesterol biosynthetic pathways. Importantly, inhibiting these pathways with specific inhibitors converted the chemo-resistant TCOs into chemo-sensitive TCOs. Conversely, autophagy activation with mTOR inhibitors conferred chemo-resistance on the chemo-sensitive TCOs. This unique model provides insights into the mechanism of MRD formation in TCs, leading to effective therapeutic approaches to reduce the recurrence of TC.

Pancreatic cancer (PC) is one of the most aggressive malignancies worldwide, and few effective therapeutics are available. Osthole (OST), a natural coumarin, has been proven to be a potential anticancer compound. In this study, we found that OST significantly inhibited PC growth both in vitro and in vivo. Notably, the anti-PC effect of OST is mediated by excessive autophagosome accumulation and consequent apoptosis in PC cells. Mechanistically, OST increased the number of autophagosomes via two pathways. First, OST induced autophagy initiation by suppressing the Akt/mTOR signaling pathway. Second, OST induced autophagic arrest by blocking autophagosome-lysosome fusion. Consistently, inhibition of autophagy initiation restored PC cell growth, whereas autophagic flux inhibitors exacerbated the antitumor effect of OST in PC cells, suggesting a cytotoxic role of OST-induced autophagosome accumulation. In addition, we found that OST upregulates the expression of activating transcription factor 3 (ATF3), resulting in inactivation of the Akt/mTOR signaling pathway and autophagy initiation in PC cells. ATF3 overexpression increased the activation of autophagy, and inhibition of ATF3 expression decreased autophagy. Taken together, our study provides new insights into the OST-induced growth inhibitory effect on PC cells, suggesting a promising potential therapeutic role of OST for PC treatment.

Autophagy is an intracellular degradation process that sequesters cytoplasmic components in double-membrane vesicles known as autophagosomes, which are degraded upon fusion with lysosomes. This pathway maintains the integrity of proteins and organelles while providing energy and nutrients to cells, particularly under nutrient deprivation. Deregulation of autophagy can cause genomic instability, low protein quality, and DNA damage, all of which can contribute to cancer. Autophagy can also be overactivated in cancer cells to aid in cancer cell survival and drug resistance. Emerging evidence indicates that autophagy has functions beyond cargo degradation, including roles in tumor immunity and cancer stem cell survival. Additionally, autophagy can also influence the tumor microenvironment. This feature warrants further investigation of the role of autophagy in cancer, in which autophagy manipulation can improve cancer therapies, including cancer immunotherapy. This review discusses recent findings on the regulation of autophagy and its role in cancer therapy and drug resistance.

This paper provides an exhaustive overview of the intricate interplay between microRNAs (miRNAs) and autophagy in the context of human cancers, underscoring the pivotal role these non-coding RNAs play in modulating autophagic pathways and their implications for cancer development, progression, and resistance to therapy. MiRNAs, as critical regulators of gene expression post-transcription, influence various biological processes, including autophagy, a catabolic mechanism essential for cellular homeostasis, stress response, and survival. The review meticulously delineates the mechanisms through which miRNAs impact autophagy by targeting specific genes and signaling pathways, thereby affecting cancer cell proliferation, metastasis, and response to chemotherapy. It highlights several miRNAs with dual roles, acting either as oncogenes or tumor suppressors based on the cellular context and the specific autophagic pathways they regulate. The paper further explores the therapeutic potential of targeting miRNA-autophagy axis, offering insights into novel strategies for cancer treatment through modulation of this axis. Emphasizing the complexity of the miRNA-autophagy relationship, the review calls for more in-depth studies to unravel the nuanced regulatory networks between miRNAs and autophagy in cancer, which could pave the way for the development of innovative therapeutic interventions and diagnostic tools.

Pancreatic cancer, characterized by a dismal prognosis and limited treatment options, persists as a formidable challenge in oncology. Trophoblast cell surface antigen 2 (TROP2)-directed antibody-drug conjugates have achieved great success in solid tumors such as breast cancer and uroepithelial carcinoma. However, their efficacy against pancreatic cancer was insufficient in clinical trials, necessitating an imperative exploration of underlying mechanisms and new therapeutic strategies. In this study, we indicated that αTROP2-MMAE, an antibody-drug conjugate targeting TROP2, induced apoptosis through the caspase-9/PARP pathway and exerted potent antitumor effects against TROP2-positive pancreatic cancer. Simultaneously, RNA sequencing suggested significant changes in autophagy after αTROP2-MMAE treatment. The formation of autophagosomes and activation of autophagic flux were markedly induced through mechanisms associated with suppressing the activation of the Akt/mTOR pathway. The addition of pharmacological inhibitors of autophagy enhanced the cytotoxicity and apoptosis caused by αTROP2-MMAE, revealing the cytoprotective role of autophagy in TROP2-positive pancreatic cancer. In the subcutaneous xenograft model using BxPC3 cells, the combined administration of αTROP2-MMAE and an autophagy inhibitor elevated the tumor inhibition rate of αTROP2-MMAE from 71.6 % to 99.0 %, resulting in the eradication of tumors in half of the mice. Collectively, our research demonstrated for the first time the cytoprotective role of autophagy in TROP2-targeted antibody-drug conjugate therapy for pancreatic cancer, providing new perspectives for mechanistic exploration and therapeutic strategies in the treatment of pancreatic cancer.

The TRIM (tripartite motif) family, with TRIM28 as a key member, plays a vital role in regulating health and disease. TRIM28 contains various functional domains essential for transcriptional regulation, primarily through its interaction with KRAB-ZNF proteins, which influence chromatin remodeling and gene expression. Despite extensive research, the precise mechanisms by which TRIM28 impacts health and disease remain elusive. This review delves into TRIM28's multifaceted roles in maintaining health, contributing to a variety of diseases, and influencing cancer progression. In cancers, TRIM28 exhibits a dual nature, functioning as both a tumor promoter and suppressor depending on the cellular context and cancer type. The review also explores its critical involvement in processes such as DNA repair, cell cycle regulation, epithelial-to-mesenchymal transition, and the maintenance of stem cell properties. By uncovering TRIM28's complex roles across different cancers and other diseases, this review underscores its potential as a therapeutic target. The significance of TRIM28 as a versatile regulator opens the door to innovative therapeutic strategies, particularly in cancer treatment and the management of other diseases. Ongoing research into TRIM28 may yield key insights into disease progression and novel treatment options.

The extracellular matrix (ECM) is a major constituent of the tumor microenvironment, acting as a mediator that supports the progression of gastrointestinal (GI) cancers, particularly in mesenchymal subtypes. Beyond providing structural support, the ECM actively shapes the tumor microenvironment (TME) through complex biochemical and biomechanical remodeling. Dysregulation of ECM composition and signaling is closely linked to increased cancer aggressiveness, poor prognosis, and resistance to therapy. ECM components, such as collagen, fibronectin, laminin, and periostin, influence tumor growth, metastasis, immune modulation, and metabolic reprogramming by interacting with tumor cells, immune cells, and cancer-associated fibroblasts. In this review, we highlight the heterogeneous nature of the ECM and the dualistic roles of its components across GI cancers, with a focus on their contributions to immune evasion and metabolic remodeling via intercellular interactions. Additionally, we explore therapeutic strategies targeting ECM remodeling and ECM-centered interactions, emphasizing their potential in enhancing existing anti-tumor therapies.

Hypoxic pulmonary hypertension (HPH) is a pulmonary vascular disease primarily characterized by progressive pulmonary vascular remodeling in a hypoxic environment, posing a significant clinical challenge. Leveraging data from the Gene Expression Omnibus (GEO) and human autophagy-specific databases, osteopontin (OPN) emerged as a differentially expressed gene, upregulated in cardiovascular diseases such as pulmonary arterial hypertension (PAH). Despite this association, the precise mechanism by which OPN regulates autophagy in HPH remains unclear, prompting the focus of this study. Through biosignature analysis, we observed significant alterations in the PI3K-AKT signaling pathway in PAH-associated autophagy. Subsequently, we utilized an animal model of OPNfl/fl-TAGLN-Cre mice and PASMCs with OPN shRNA to validate these findings. Our results revealed right ventricular hypertrophy and elevated mean pulmonary arterial pressure (mPAP) in hypoxic pulmonary hypertension model mice. Notably, these effects were attenuated in conditionally deleted OPN-knockout mice or OPN-silenced hypoxic PASMCs. Furthermore, hypoxic PASMCs with OPN shRNA exhibited increased autophagy compared to those in hypoxia alone. Consistent findings from in vivo and in vitro experiments indicated that OPN inhibition during hypoxia reduced PI3K expression while increasing LC3B and Beclin1 expression. Similarly, PASMCs exposed to hypoxia and PI3K inhibitors had higher expression levels of LC3B and Beclin1 and suppressed AKT expression. Based on these findings, our study suggests that OPNfl/fl-TAGLN-Cre effectively alleviates HPH, potentially through OPN-mediated inhibition of autophagy, thereby promoting PASMCs proliferation via the PI3K-AKT signaling pathway. Consequently, OPN emerges as a novel therapeutic target for HPH.

Tumors are composed of heterogeneous populations of dysregulated cells that grow in specialized niches that support their growth and maintain their properties. Tumor heterogeneity and metastasis are among the major hindrances that exist while treating cancer patients, leading to poor clinical outcomes. Although the factors that determine tumor complexity remain largely unknown, several genotypic and phenotypic changes, including DNA mutations and metabolic reprograming provide cancer cells with a survival advantage over host cells and resistance to therapeutics. Furthermore, the presence of a specific population of cells within the tumor mass, commonly known as cancer stem cells (CSCs), is thought to initiate tumor formation, maintenance, resistance, and recurrence. Therefore, these CSCs have been investigated in detail recently as potential targets to treat cancer and prevent recurrence. Understanding the molecular mechanisms involved in CSC proliferation, self-renewal, and dormancy may provide important clues for developing effective therapeutic strategies. Autophagy, a catabolic process, has long been recognized to regulate various physiological and pathological processes. In addition to regulating cancer cells, recent studies have identified a critical role for autophagy in regulating CSC functions. Autophagy is activated under various adverse conditions and promotes cellular maintenance, survival, and even cell death. Thus, it is intriguing to address whether autophagy promotes or inhibits CSC functions and whether autophagy modulation can be used to regulate CSC functions, either alone or in combination. This review describes the roles of autophagy in the regulation of metabolic functions, proliferation and quiescence of CSCs, and its role during therapeutic stress. The review further highlights the autophagy-associated pathways that could be used to regulate CSCs. Overall, the present review will help to rationalize various translational approaches that involve autophagy-mediated modulation of CSCs in controlling cancer progression, metastasis, and recurrence.

Gemcitabine (GEM) resistance affects chemotherapy efficacy of pancreatic cancer (PC). Cancer-associated fibroblasts (CAFs) possess the ability of regulating chemoresistance. This study probed the mechanism of hypoxia-treated CAFs regulating cell stemness and GEM resistance in PC. Miapaca-2/SW1990 were co-cultured with PC-derived CAFs under normoxic/hypoxic conditions. Cell viability/self-renewal ability was determined by MTT/sphere formation assays, respectively. Protein levels of CD44, CD133, Oct4, and Sox2 were determined by western blot. GEM tumoricidal assay was performed. PC cell GEM resistance was evaluated by MTT assay. CAFs were cultured at normoxia/hypoxia. HIF-1α and miR-21 expression levels were assessed by RT-qPCR and western blot, with their binding sites and binding relationship predicted and verified. CAF-extracellular vesicles (EVs) were incubated with Miapaca-2 cells. The RAS/AKT/ERK pathway activation was detected by western blot. PC xenograft models were established and treated with hypoxic CAF-EVs and GEM. CAFs and PC cell co-culture increased cell stemness maintenance, GEM resistance, cell viability, stem cell sphere number, and protein levels of CD44, CD133, Oct4, and Sox2, and weakened GEM tumoricidal ability to PC cells, with the effects further enhanced by hypoxia. Hypoxia induced HIF-1α and miR-21 overexpression in CAFs. Hypoxia promoted CAFs to secrete high-level miR-21 EVs via the HIF-1α/miR-21 axis, and activated the miR-21/RAS/AKT/ERK pathway. CAF-EVs promoted GEM resistance in PC via the miR-21/RAS/ATK/ERK pathway in vivo. Hypoxia promoted CAFs to secrete high-level miR-21 EVs through the HIF-1α/miR-21 axis, and activated the miR-21/RAS/AKT/ERK pathway via EVs to trigger stemness maintenance and GEM resistance in PC.

Autophagy is a self-digestion multistep process in which causes the homeostasis through degradation of macromolecules and damaged organelles. The autophagy-mediated tumor progression regulation has been a critical point in recent years, revealing the function of this process in reduction or acceleration of carcinogenesis. Leukemia is a haematological malignancy in which abnormal expansion of hematopoietic cells occurs. The current and conventional therapies from chemotherapy to cell transplantation have failed to appropriately treat the leukemia patients. Among the mechanisms dysregulated in leukemia, autophagy is a prominent one in which can regulate the hallmarks of this tumor. The protective autophagy inhibits apoptosis and ferroptosis in leukemia, while toxic autophagy accelerates cell death. The proliferation and invasion of tumor cells are tightly regulated by the autophagy. The direction of regulation depends on the function of autophagy that is protective or lethal. The protective autophagy accelerates chemoresistance and radio-resistsance. The non-coding RNAs, histone transferases and other pathways such as PI3K/Akt/mTOR are among the regulators of autophagy in leukemia progression. The pharmacological intervention for the inhibition or induction of autophagy by the compounds including sesamine, tanshinone IIA and other synthetic compounds can chance progression of leukemia.

Chemoresistance is an obstacle of improving pancreatic cancer (PC) prognosis. However, the biological function of ISG15 in PC and whether it correlates with the resistance to chemotherapy are still unknown. Here, we aimed to reveal the clinical significance of ISG15 in PC and its regulatory mechanism in cancer progression and resistance to therapy. The level of ISG15, a protein involved in post-translational modifications, is elevated in PC tissues. Clinically, higher ISG15 expression correlates with higher PC grades, stronger resistance to treatment and poorer prognosis. Moreover, ISG15 promotes the proliferation, migration, invasion, colony formation of PC cells and resistance to Gemcitabine, a classic chemotherapeutics for PC, both in vitro and in vivo. ISG15 promotes progression and resistance to therapy in PC cells by binding to ATG7, reducing its degradation, and thereby leading to enhanced autophagy in PC cells. ISG15 may be used as both a potential diagnosis marker and sensitizer for chemotherapeutics such as Gemcitabine during PC intervention.

We recently demonstrated that a small subset of cells in FLT3-mutated acute myeloid leukemia (AML) cell lines exhibit SORE6 reporter activity and cancer stem-like features including chemoresistance. To study why SORE6+ cells are more chemoresistant than SORE6- cells, we hypothesized that these cells carry higher autophagy, a mechanism linked to chemoresistance. We found that cytarabine (Ara-C) induced a substantially higher protein level of LC3B-II in SORE6+ compared to SORE6- cells. Similar observations were made using a fluorescence signal-based autophagy assay. Furthermore, chloroquine (an autophagy inhibitor) sensitized SORE6+ but not SORE6- cells to Ara-C. To decipher the molecular mechanisms underlying the high autophagic flux in SORE6+ cells, we employed an autophagy oligonucleotide array comparing gene expression between SORE6+ and SORE6- cells before and after Ara-C treatment. ULK2 was the most differentially expressed gene between the two cell subsets. To demonstrate the role of ULK2 in conferring higher chemoresistance in SORE6+ cells, we treated the two cell subsets with a ULK1/2 inhibitor, MRT68921. MRT68921 significantly sensitized SORE6+ but not SORE6- cells to Ara-C. Using our in vitro model for AML relapse, we found that regenerated AML cells contained higher ULK2 expression compared to pretreated cells. Importantly, inhibition of ULK2 using MRT68921 prevented in vitro AML relapse. Lastly, using pretreatment and relapsed AML patient bone marrow samples, we found that ULK2 expression was higher in relapsed AML. To conclude, our results supported the importance of autophagy in the relapse of FLT3-mutated AML and highlighted ULK2 in this context.

A high number of cancer patients around the world rely on gemcitabine (GEM) for chemotherapy. During local metastasis of cancers, surgery is beneficial for therapy, but dissemination in distant organs leads to using chemotherapy alone or in combination with surgery to prevent cancer recurrence. Therapy failure can be observed as a result of GEM resistance, threatening life of pancreatic cancer (PC) patients. The mortality and morbidity of PC in contrast to other tumors are increasing. GEM chemotherapy is widely utilized for PC suppression, but resistance has encountered its therapeutic impacts. The purpose of current review is to bring a broad concept about role of biological mechanisms and pathways in the development of GEM resistance in PC and then, therapeutic strategies based on using drugs or nanostructures for overcoming chemoresistance. Dysregulation of the epigenetic factors especially non-coding RNA transcripts can cause development of GEM resistance in PC and miRNA transfection or using genetic tools such as siRNA for modulating expression level of these factors for changing GEM resistance are suggested. The overexpression of anti-apoptotic proteins and survival genes can contribute to GEM resistance in PC. Moreover, supportive autophagy inhibits apoptosis and stimulates GEM resistance in PC cells. Increase in metabolism, glycolysis induction and epithelial-mesenchymal transition (EMT) stimulation are considered as other factors participating in GEM resistance in PC. Drugs can suppress tumorigenesis in PC and inhibit survival factors and pathways in increasing GEM sensitivity in PC. More importantly, nanoparticles can increase pharmacokinetic profile of GEM and promote its blood circulation and accumulation in cancer site. Nanoparticles mediate delivery of GEM with genes and drugs to suppress tumorigenesis in PC and increase drug sensitivity. The basic research displays significant connection among dysregulated pathways and GEM resistance, but the lack of clinical application is a drawback that can be responded in future.

Breast cancer (BC) is among the most prevalent aggressive type of malignancy affecting females worldwide. Despite the advance in early detection and management of BC; recurrence, metastasis and mortality remains high. This may be attributed to heterogeneity of BC which explained by the presence of breast cancer stem cells (BCSCs). BCSCs is characterized by their ability of self-renewal, unlimited proliferation and their differentiation potential.  BCSCs maintain their activity through process of autophagy. Autophagy is a catabolic pathway important for maintenance of cellular hemostasis in response to different stressful conditions. Autophagy allows BCSCs to adapt to different stressful conditions. So, it protects BCSCs from cytotoxic effects of anti-cancer therapy and anticancer resistance.

Formalin-fixed paraffin embedded fifty specimens of Invasive duct carcinoma of no special type(IDC/NST) of breast was selected and immunostained with stem cell marker CD44 and autophagy related marker LC3B antibodies. Correlation with different clinicopathological, histopathological characteristics and molecular subtypes of studied specimens were evaluated.

Both CD44 and LC3B expression were significantly associated with lymph nodal metastasis (p =0.001 and 0.010 respectively), advanced pathological stage (p= 0.045 and 0.004 respectively) and with triple negative molecular subtype of BC (p=0.044 and 0.048 respectively). Statistically positive correlation was also found between both tumor markers expression.

Results of this study suggests that CD44 and LC3B expression play a role in the clinical behavior and progression of different molecular subtypes of BC.

Cancer stem cells (CSCs) are considered tumor-initiating cells and the main drivers of disease progression. Targeting these rare cancer cells, however, remains challenging with respect to therapeutic benefit. Here, we report the up-regulation of IL-13RA2 expression in colorectal cancer (CRC) tissues and spheroid cells. The expression of IL-13RA2 was positively correlated with canonical stemness markers in CRC. We further demonstrated that the level of IL-13 was up-regulated in the serum of CRC patients. Biologically, recombinant IL-13 (rIL-13) stimulation promoted the sphere formation, proliferation, and migration of CRC cells in vitro and enhanced tumorigenesis in vivo. This phenotype could be reversed by knocking down IL-13RA2. Mechanistically, IL-13 activated autophagy by inducing LC3I/LC3II transformation in CRC-CSCs, which was crucial for the biological functions of IL-13. We further demonstrated that IL-13RA2 acted as a modular link of the E3 ligase UBE3C and the substrate p53 protein, enhancing the interaction of UBE3C and p53, thereby inducing the K48-linked ubiquitination of p53. In conclusion, the IL-13/IL-13RA2 signaling cascade promotes CRC-CSC self-renewal and tumorigenesis by inducing p53 ubiquitination, adding an important layer to the connection between IL-13 and p53, which can be translated into novel targeted therapies.

Pancreatic cancer is highly lethal, of which 90% is pancreatic ductal adenocarcinoma (PDAC), with a 5-year survival rate of less than 12%, lacking effective treatment options and late diagnosis. Furthermore, the tumors show an intense resistance to cytotoxic chemotherapies. As autophagy is elevated in PDAC, targeting the autophagic pathway is regarded as a promising strategy for cancer treatment. Immunofluorescence and transmission electron microscopy were utilized to assess the autophagic flux. Label-free quantitative phosphoproteomics was used to figure out critically altered tyrosine phosphorylation of the proteins. Tumor-bearing mice were used to validate that SH2 TrM-(Arg)9 restrained the growth of tumor cells. SH2 TrM-(Arg)9 inhibited collagen-induced autophagy via blocking the DDR1/PYK2/ERK signaling cascades. SH2 TrM-(Arg)9 improved the sensitivity of PANC-1/GEM cells to gemcitabine (GEM). Inhibition of autophagy by SH2 TrM-(Arg)9 may synergized with chemotherapy and robusted tumor suppression in pancreatic cancer xenografts. SH2 TrM-(Arg)9 could enter into PDAC cells and blockade autophagy through inhibiting DDR1/PYK2/ERK signaling and may be a new treatment strategy for targeted therapy of PDAC.

Pancreatic cancer, notorious for its late diagnosis and aggressive progression, poses a substantial challenge owing to scarce treatment alternatives. This review endeavors to furnish a holistic insight into pancreatic cancer, encompassing its epidemiology, genomic characterization, risk factors, diagnosis, therapeutic strategies, and treatment resistance mechanisms. We delve into identifying risk factors, including genetic predisposition and environmental exposures, and explore recent research advancements in precursor lesions and molecular subtypes of pancreatic cancer. Additionally, we highlight the development and application of multi-omics approaches in pancreatic cancer research and discuss the latest combinations of pancreatic cancer biomarkers and their efficacy. We also dissect the primary mechanisms underlying treatment resistance in this malignancy, illustrating the latest therapeutic options and advancements in the field. Conclusively, we accentuate the urgent demand for more extensive research to enhance the prognosis for pancreatic cancer patients.

Rhabdomyosarcoma is a rare cancer arising in skeletal muscle that typically impacts children and young adults. It is a worldwide challenge in child health as treatment outcomes for metastatic and recurrent disease still pose a major concern for both basic and clinical scientists. The treatment strategies for rhabdomyosarcoma include multi-agent chemotherapies after surgical resection with or without ionization radiotherapy. In this comprehensive review, we first provide a detailed clinical understanding of rhabdomyosarcoma including its classification and subtypes, diagnosis, and treatment strategies. Later, we focus on chemotherapy strategies for this childhood sarcoma and discuss the impact of three mechanisms that are involved in the chemotherapy response including apoptosis, macro-autophagy, and the unfolded protein response. Finally, we discuss in vivo mouse and zebrafish models and in vitro three-dimensional bioengineering models of rhabdomyosarcoma to screen future therapeutic approaches and promote muscle regeneration.

Cancer stem cell (CSC) populations are regulated by autophagy, which in turn modulates tumorigenicity and malignancy. In this study, we demonstrated that cisplatin treatment enriches the CSCs population by increasing autophagosome formation and speeding up autophagosome-lysosome fusion by recruiting RAB7 to autolysosomes. Further, cisplatin treatment stimulates lysosomal activity and increases autophagic flux in oral CD44+ cells. Interestingly, both ATG5- and BECN1-dependent autophagy are essential for maintaining cancer stemness, self-renewal, and resistance to cisplatin-induced cytotoxicity in oral CD44+ cells. Moreover, we discovered that autophagy-deficient (shATG5 and/or shBECN1) CD44+ cells activates nuclear factor, erythroid 2 like 2 (NRF2) signaling, which in turn reduces the elevated reactive oxygen species (ROS) level enhancing cancer stemness. Genetic inhibition of NRF2 (siNRF2) in autophagy-deficient CD44+ cells increases mitochondrial ROS (mtROS) level, reducing cisplatin-resistance CSCs, and pre-treatment with mitoTEMPO [a mitochondria-targeted superoxide dismutase (SOD) mimetic] lessened the cytotoxic effect enhancing cancer stemness. We also found that inhibiting autophagy (with CQ) and NRF2 signaling (with ML-385) combinedly increases cisplatin cytotoxicity, thereby suppressing the expansion of oral CD44+ cells; this finding has the potential to be clinically applicable in resolving CSC-associated chemoresistance and tumor relapse in oral cancer.

Pancreatic ductal adenocarcinoma (PDAC) features high recurrence rates and intensified lethality, accompanied by stiffening of the extracellular matrix (ECM) microenvironment, which is mainly due to the deposition, remodeling, and cross-linking of collagen. Boosted stemness plays an essential role during occurrence and progression, which indicates a poor prognosis. Therefore, it is of great importance to understand the effect of the underlying interaction of matrix stiffness and stemness on PDAC. For this purpose, a methacrylated gelatin (GelMA) hydrogel with tunable stiffness was applied for incubating MIA PaCa-2 and PANC-1 cells. The results demonstrated that compared to the soft group (5% GelMA, w/v), the expression of stemness-related genes (SOX2, OCT4, and NANOG) in the stiff group (10% GelMA, w/v) displayed pronounced elevation as well as sphere formation. Intriguingly, we also observed that matrix stiffness regulated autophagy of PDAC, which played a momentous role in stemness promotion. In order to clarify the underlying relationship between matrix stiffness-mediated cell autophagy and stemness, rescue experiments with rapamycin and chloroquine were conducted with transmission electron microscopy, immunofluorescence staining, sphere formation, and qRT-PCR assays to evaluate the level of stemness and autophagy. For exploring the molecular mechanism in depth, RNA-seq and differential expression of miRNAs were carried out, which may sensor and respond to matrix stiffness during the regulation of stemness and autophagy. In conclusion, we validated that blocking autophagy repressed the stemness induced by matrix stiffness in PDAC and provided a potential therapeutic strategy for this aggressive cancer.

Chemotherapy is widely used as one of the first line therapeutic methods in cancer patients. However, chemotherapeutic resistance is one of the most common problems in cancer patients, which leads to the therapeutic failure and tumor relapse. Considering the side effects of chemotherapy drugs in normal tissues, it is required to investigate the molecular mechanisms involved in drug resistance to improve the therapeutic strategies in cancer patients. Long non-coding RNAs (lncRNAs) have pivotal roles in regulation of cellular processes associated with drug resistance. LncRNAs deregulations have been frequently reported in a wide range of chemo-resistant tumors. Gemcitabine (GEM) as a nucleoside analog has a wide therapeutic application in different cancers. However, GEM resistance is considered as a therapeutic challenge. Considering the role of lncRNAs in the occurrence of GEM resistance, in the present review we discussed the molecular mechanisms of lncRNAs in regulation of GEM response among cancer patients. It has been reported that lncRNAs have mainly an oncogenic role as the inducers of GEM resistance through direct or indirect regulation of transcription factors, autophagy, polycomb complex, and signaling pathways such as PI3K/AKT, MAPK, WNT, JAK/STAT, and TGF-β. This review paves the way to present the lncRNAs as non-invasive markers to predict GEM response in cancer patients. Therefore, lncRNAs can be introduced as the efficient markers to reduce the possible chemotherapeutic side effects in GEM resistant cancer patients and define a suitable therapeutic strategy among these patients.

Gemcitabine resistance (GR) is a significant clinical challenge in pancreatic adenocarcinoma (PAAD) treatment. Macrophages in the tumor immune-microenvironment are closely related to GR. Uncovering the macrophage-induced GR mechanism could help devise a novel strategy to improve gemcitabine treatment outcomes in PAAD. Therefore, preclinical models accurately replicating patient tumor properties are essential for cancer research and drug development. Patient-derived organoids (PDOs) represent a promising in vitro model for investigating tumor targets, accelerating drug development, and enabling personalized treatment strategies to improve patient outcomes.

To investigate the effects of macrophage stimulation on GR, co-cultures were set up using PDOs from three PAAD patients with macrophages. To identify signaling factors between macrophages and pancreatic cancer cells (PCCs), a 97-target cytokine array and the TCGA-GTEx database were utilized. The analysis revealed CCL5 and AREG as potential candidates. The role of CCL5 in inducing GR was further investigated using clinical data and tumor sections obtained from 48 PAAD patients over three years, inhibitors, and short hairpin RNA (shRNA). Furthermore, single-cell sequencing data from the GEO database were analyzed to explore the crosstalk between PCCs and macrophages. To overcome GR, inhibitors targeting the macrophage-CCL5-Sp1-AREG feedback loop were evaluated in cell lines, PDOs, and orthotopic mouse models of pancreatic carcinoma.

The macrophage-CCL5-Sp1-AREG feedback loop between macrophages and PCCs is responsible for GR. Macrophage-derived CCL5 activates the CCR5/AKT/Sp1/CD44 axis to confer stemness and chemoresistance to PCCs. PCC-derived AREG promotes CCL5 secretion in macrophages through the Hippo-YAP pathway. By targeting the feedback loop, mithramycin improves the outcome of gemcitabine treatment in PAAD. The results from the PDO model were corroborated with cell lines, mouse models, and clinical data.

Our study highlights that the PDO model is a superior choice for preclinical research and precision medicine. The macrophage-CCL5-Sp1-AREG feedback loop confers stemness to PCCs to facilitate gemcitabine resistance by activating the CCR5/AKT/SP1/CD44 pathway. The combination of gemcitabine and mithramycin shows potential as a therapeutic strategy for treating PAAD in cell lines, PDOs, and mouse models.

Autophagy is a dynamic intracellular process of protein degradation, which is mostly triggered by nutrient deprivation. This process initiates with the formation of autophagosomes, which they capture cytosolic material that is then degraded upon fusion with the lysosome. Several factors have been found to be associated with autophagy modulation, of which extracellular matrix (ECM) components has attracted the attention of recent studies. Osteopontin (OPN) is an important extracellular matrix component that has been detected in a wide range of tumor cells, and is involved in cancer cell invasion and metastasis. Recently, a number of studies have focused on the relationship of OPN with autophagy, by delineating the intracellular signaling pathways that connect OPN to the autophagy process. We will summarize signaling pathways and cell surface receptors, through which OPN regulates the process of autophagy.

Pancreatic cancer (PC) is a serious gastrointestinal tract disease for which the 5-year survival rate is less than 10%, even in developed countries such as the USA. The genomic profile alterations and dysregulated biological mechanisms commonly occur in PC. Macroautophagy/autophagy is a cell death process that is maintained at a basal level in physiological conditions, whereas its level often changes during tumorigenesis. The function of autophagy in human cancers is dual and can be oncogenic and onco-suppressor. Autophagy is a potent controller of tumorigenesis in PC. The supportive autophagy in PC escalates the growth rate of PC cells and its suppression can mediate cell death. Autophagy also determines the metastasis of PC cells, and it can control the EMT in affecting migration. Moreover, starvation and hypoxia can stimulate glycolysis, and glycolysis induction can be mediated by autophagy in enhancing tumorigenesis in PC. Furthermore, protective autophagy stimulates drug resistance and gemcitabine resistance in PC cells, and its inhibition can enhance radiosensitivity. Autophagy can degrade MHC-I to mediate immune evasion and also regulates polarization of macrophages in the tumor microenvironment. Modulation of autophagy activity is provided by silibinin, ursolic acid, chrysin and huaier in the treatment of PC. Non-coding RNAs are also controllers of autophagy in PC and its inhibition can improve therapy response in patients. Moreover, mitophagy shows dysregulation in PC, which can enhance the proliferation of PC cells. Therefore, a bioinformatics analysis demonstrates the dysregulation of autophagy-related proteins and genes in PC as biomarkers.

Cancer stem cells(CSCs) play a key role in regulating tumorigenesis, progression, as well as recurrence, and possess typical metabolic characteristics. Autophagy is a catabolic process that can aid cells to survive under stressful conditions such as nutrient deficiency and hypoxia. Although the role of autophagy in cancer cells has been extensively studied, CSCs possess unique stemness, and their potential relationship with autophagy has not been fully analyzed. This study summarizes the possible role of autophagy in the renewal, proliferation, differentiation, survival, metastasis, invasion, and treatment resistance of CSCs. It has been found that autophagy can contribute to the maintenance of CSC stemness, facilitate the tumor cells adapt to changes in the microenvironment, and promote tumor survival, whereas in some other cases autophagy acts as an important process involved in the deprivation of CSC stemness thus leading to tumor death. Mitophagy, which has emerged as another popular research area in recent years, has a great scope when explored together with stem cells. In this study, we have aimed to elaborate on the mechanism of action of autophagy in regulating the functions of CSCs to provide deeper insights for future cancer treatment.

Pancreatic adenocarcinoma (PAAD) is the most malignant cancer with a high mortality rate. Despite the association of ribosomal protein L10 (RPL10) with PAAD and previous reports on RPL26 ufmylation, the relationship between RPL10 ufmylation and PAAD development remains unexplored. Here, we report the dissection of ufmylating process of RPL10 and potential roles of RPL10 ufmylation in PAAD development. The ufmylation of RPL10 was confirmed in both pancreatic patient tissues and cell lines, and specific modification sites were identified and verified. Phenotypically, RPL10 ufmylation significantly increased cell proliferation and stemness, which is principally resulted from higher expression of transcription factor KLF4. Moreover, the mutagenesis of ufmylation sites in RPL10 further demonstrated the connection of RPL10 ufmylation with cell proliferation and stemness. Collectively, this study reveals that PRL10 ufmylation plays an important role to enhance the stemness of pancreatic cancer cells for PAAD development.

Cancer stem cells (CSCs) are a subset of cancer cells with self-renewal ability and tumor initiating properties. Unlike the other non-stem cancer cells, CSCs resist traditional therapy and remain a major cause of disease relapse. With the recent advances in metabolomics, various studies have demonstrated that CSCs have distinct metabolic properties. Metabolic reprogramming in CSCs contributes to self-renewal and maintenance of stemness. Accumulating evidence suggests that rewiring of energy metabolism is a key player that enables to meet energy demands, maintains stemness, and sustains cancer growth and invasion. CSCs use various mechanisms such as increased glycolysis, redox signaling, and autophagy modulation to overcome nutritional deficiency and sustain cell survival. The alterations in lipid metabolism acquired by the CSCs support biomass production through increased dependence on fatty acid synthesis and β-oxidation, and contribute to oncogenic signaling pathways. This review summarizes our current understanding of lipid metabolism in CSCs and how pharmacological regulation of autophagy and lipid metabolism influences CSC phenotype. Increased dependence on lipid metabolism appears as an attractive strategy to eliminate CSCs using therapeutic agents that specifically target CSCs based on their modulation of lipid metabolism.

Cancer stem cells are found in many cancer types. They comprise a distinct subpopulation of cells within the tumor that exhibit properties of stem cells. They express a number of cell surface markers, such as CD133, CD44, ALDH, and EpCAM, as well as embryonic transcription factors Oct4, Nanog, and SOX2. CSCs are more resistant to conventional chemotherapy and can potentially drive tumor relapse. Therefore, it is essential to understand the molecular mechanisms that drive chemoresistance and to target them with specific therapy effectively. Highly conserved developmental signaling pathways such as Wnt, Hedgehog, and Notch are commonly reported to play a role in CSCs chemoresistance development. Studies show that particular pathway inhibitors combined with conventional therapy may re-establish sensitivity to the conventional therapy. Another significant contributor of chemoresistance is a specific tumor microenvironment. Surrounding stroma in the form of cancer-associated fibroblasts, macrophages, endothelial cells, and extracellular matrix components produce cytokines and other factors, thus creating a favorable environment and decreasing the cytotoxic effects of chemotherapy. Anti-stromal agents may potentially help to overcome these effects. Epigenetic changes and autophagy were also among the commonly reported mechanisms of chemoresistance. This review provides an overview of signaling pathway components involved in the development of chemoresistance of CSCs and gathers evidence from experimental studies in which CSCs can be re-sensitized to conventional chemotherapy agents across different cancer types.

Cancer is one of the leading causes of mortality worldwide. Currently, drug resistance is the main obstacle in cancer treatments with the underlying mechanisms of drug resistance yet to be fully understood. Osteopontin (OPN) is a member of the integrin binding glycophosphoprotein family that is overexpressed in several tumour types. It is involved in drug transport, apoptosis, stemness, energy metabolism, and autophagy, which may contribute to drug resistance. Thus, understanding the role of OPN in cancer drug resistance could be important. This review describes the OPN-based mechanisms that might contribute to cancer drug resistance, demonstrating that OPN may be a viable target for cancer therapy to reduce drug resistance in sensitive tumours.

Pancreatic cancer (PC) is a malignancy accounting for only 3% of total cancers, but with a low 5-year relative survival rate. Approximately 80% of PC patients are diagnosed at a late stage when the disease has already spread from the primary site. Despite advances in PC treatment, there is an urgently needed for the identification of novel therapeutic strategies for PC, particularly for patients who cannot undergo classical surgery. Autophagy is an evolutionarily conserved process used by cells to adapt to metabolic stress via the degrading or recycling of damaged or unnecessary organelles and cellular components. This process is elevated in PC and, thus, it contributes to the onset, progression, and cancer cell resistance to chemotherapy in pancreatic tumors. Autophagy inhibition has been shown to lead to cancer regression and to increase the sensitivity of pancreatic cells to radiation and chemotherapy. Emerging studies have focused on the roles of non-coding RNAs (ncRNAs), such as miRNAs, long non-coding RNAs, and circular RNAs, in PC development and progression. Furthermore, ncRNAs have been reported as crucial regulators of many biological processes, including autophagy, suggesting that ncRNA-based autophagy targeting methods could be promising novel molecular approaches for specifically reducing autophagic flux, thus improving the management of PC patients. In this review, we briefly summarize the existing studies regarding the role and the regulatory mechanisms of autophagy-related ncRNAs in the context of this cancer.

Cr(VI) is broadly applied in industry. Cr(VI) exposure places a big burden on public health, thereby increasing the risk of lung squamous cell carcinoma (LUSC). The mechanisms underlying Cr(VI)-induced LUSC remain largely elusive. Here, we report that the cancer stem cell (CSC)/tumour-initiating cell (TIC)-like subgroup within Cr(VI)-transformed bronchial epithelial cells (CrT) promotes lung cancer tumourigenesis. Mechanistically, Cr(VI) exposure specifically increases the expression levels of aldehyde dehydrogenase 1A1 (ALDH1A1), a CSC marker, through KLF4-mediated transcription. ALDH1A1 maintains self-renewal of CrT/TICs and facilitates the expression and secretion of EGF from CrT/TICs, which subsequently promotes the activation of EGFR signalling in differentiated cancer cells and tumour growth of LUSC. In addition, the ALDH1A1 inhibitor A37 and gemcitabine synergistically suppress LUSC progression. Importantly, high ALDH1A1 expression levels are positively correlated with advanced clinical stages and predict poor survival in LUSC patients. These findings elucidate how ALDH1A1 modulates EGF secretion from TICs to facilitate LUSC tumourigenesis, highlighting new therapeutic strategies for malignant lung cancers.

Pancreatic cancer is currently the seventh leading cause of cancer-related deaths worldwide, with the estimated death toll approaching half a million annually. Pancreatic ductal adenocarcinoma (PDAC) is the most common (>90% of cases) and most aggressive form of pancreatic cancer, with extremely poor prognosis and very low survival rates. PDAC is initiated by genetic alterations, usually in the oncogene KRAS and tumor suppressors CDKN2A, TP53 and SMAD4, which in turn affect a number of downstream signaling pathways that regulate important cellular processes. One of the processes critically altered is autophagy, the mechanism by which cells clear away and recycle impaired or dysfunctional organelles, protein aggregates and other unwanted components, in order to achieve homeostasis. Autophagy plays conflicting roles in PDAC and has been shown to act both as a positive effector, promoting the survival of pancreatic tumor-initiating cells, and as a negative effector, increasing cytotoxicity in uncontrollably expanding cells. Recent findings have highlighted the importance of cancer stem cells in PDAC initiation, progression and metastasis. Pancreatic cancer stem cells (PaCSCs) comprise a small subpopulation of the pancreatic tumor, characterized by cellular plasticity and the ability to self-renew, and autophagy has been recognised as a key process in PaCSC maintenance and function, simultaneously suggesting new strategies to achieve their selective elimination. In this review we evaluate recent literature that links autophagy with PaCSCs and PDAC, focusing our discussion on the therapeutic implications of pharmacologically targeting autophagy in PaCSCs, as a means to treat PDAC.

Chloroquine (CQ) and Hydroxychloroquine (HCQ), initially utilized in the treatment of malaria, have now developed a long list of applications. Despite their clinical relevance, their mechanisms of action are not clearly defined. Major pathways by which these agents are proposed to function include alkalinization of lysosomes and endosomes, downregulation of C-X-C chemokine receptor type 4 (CXCR4) expression, high-mobility group box 1 protein (HMGB1) inhibition, alteration of intracellular calcium, and prevention of thrombus formation. However, there is conflicting data present in the literature. This is likely the result of the complex overlapping pathways between these mechanisms of action that have not previously been highlighted. In fact, prior research has focused on very specific portions of particular pathways without describing these in the context of the extensive CQ/HCQ literature. This review summarizes the detailed data regarding CQ/HCQ's mechanisms of action while also providing insight into the overarching themes. Furthermore, this review provides clinical context to the application of these diverse drugs including their role in malaria, autoimmune disorders, cardiovascular disease, thrombus formation, malignancies, and viral infections.

Intratumour heterogeneity (ITH) has become an important focus of cancer research in recent years. ITH describes the cellular variation that enables tumour evolution, including tumour progression, metastasis and resistance to treatment. The selection and expansion of genetically distinct treatment-resistant cancer cell clones provides one explanation for treatment failure. However, tumour cell variation need not be genetically encoded. In pancreatic ductal adenocarcinoma (PDAC) in particular, the complex tumour microenvironment as well as crosstalk between tumour and stromal cells result in exceptionally variable tumour cell phenotypes that are also highly adaptable. In this review we discuss four different types of phenotypic heterogeneity within PDAC, from morphological to metabolic heterogeneity. We suggest that these different types of ITH are not independent, but, rather, can inform one another. Lastly, we highlight recent findings that suggest how therapeutic efforts may halt PDAC progression by constraining cellular heterogeneity.