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Chemokines are well equipped with chemo-attractive signals that can regulate cancer cell trafficking to specific organ sites. Currently, updated concepts have revealed the diverse role of chemokines in the biology of cancer initiation and progression. Genomic instabilities and alterations drive tumor heterogeneity, providing more options for the selection and metastatic progression to cancer cells. Tumor heterogeneity and acquired drug resistance are the main obstacles in managing cancer therapy and the primary root cause of metastasis. Studies emphasize that multiple chemokine/receptor axis are involved in cancer cell-mediated organ-specific distant metastasis. One of the persuasive mechanisms for heterogeneity and subsequent events is sturdily interlinked with the crosstalk between chemokines and their receptors on cancer cells and tissue-specific microenvironment. Among different metastatic niches, skeletal metastasis is frequently observed in the late stages of prostate, breast, and lung cancer and significantly reduces the survival of cancer patients. Therefore, it is crucial to elucidate the role of chemokines and their receptors in metastasis and bone remodeling. Here, we review the potential chemokine/receptor axis in tumorigenesis, tumor heterogeneity, metastasis, and vicious cycle in bone microenvironment.

MUC16, membrane-bound mucin, plays an oncogenic role in pancreatic ductal adenocarcinoma (PDAC). However, the pathological role of MUC16 in the PDAC progression, tumor microenvironment, and metastasis in cooperation with Kras(G12D) and Trp53(R172H) mutations remains unknown. Deletion of Muc16 with activating mutations Kras(G12D/+) and Trp53(R172H/+) in mice significantly decreased progression and prolonged overall survival in Kras(G12D/+); Trp53(R172H/+); Pdx-1-Cre; Muc16(−/−) (KPCM) and Kras(G12D/+); Pdx-1-Cre; Muc16(−/−) (KCM), as compared to Kras(G12D/+); Trp53(R172H/+); Pdx-1-Cre (KPC) and Kras(G12D/+); Pdx-1-Cre (KC) mice, respectively. Muc16 knockout pancreatic tumor (KPCM) displays decreased tumor microenvironment factors and significantly reduced incidence of liver and lung metastasis compared to KPC. Furthermore, in silico data analysis showed a positive correlation of MUC16 with activated stroma and metastasis- associated genes. KPCM mouse syngeneic cells had significantly lower metastatic and endothelial cell binding abilities than KPC cells. Similarly, KPCM organoids significantly decreased the growth rate than KPC organoids. Interestingly, RNA-seq data revealed that the cytoskeletal proteins Actg2, Myh11, and Pdlim3 were downregulated in KPCM tumors. Further knockdown of these genes showed reduced metastatic potential. Overall, our results demonstrate that Muc16 alters the tumor microenvironment factors during pancreatic cancer progression and metastasis by changing the expression of Actg2, Myh11, and Pdlim3 genes.

Small cell lung cancer (SCLC) is a particular subtype of lung cancer with high mortality. Recent advances in understanding SCLC genomics and breakthroughs of immunotherapy have substantially expanded existing knowledge and treatment modalities. However, challenges associated with SCLC remain enigmatic and elusive. Most of the conventional drug discovery approaches targeting altered signaling pathways in SCLC end up in the ‘grave-yard of drug discovery’, which mandates exploring novel approaches beyond inhibiting cell signaling pathways. Epigenetic modifications have long been documented as the key contributors to the tumorigenesis of almost all types of cancer, including SCLC. The last decade witnessed an exponential increase in our understanding of epigenetic modifications for SCLC. The present review highlights the central role of epigenetic regulations in acquiring neoplastic phenotype, metastasis, aggressiveness, resistance to chemotherapy, and immunotherapeutic approaches of SCLC. Different types of epigenetic modifications (DNA/histone methylation or acetylation) that can serve as predictive biomarkers for prognostication, treatment stratification, neuroendocrine lineage determination, and development of potential SCLC therapies are also discussed. We also review the utility of epigenetic targets/epidrugs in combination with first-line chemotherapy and immunotherapy that are currently under investigation in preclinical and clinical studies. Altogether, the information presents the inclusive landscape of SCLC epigenetics and epidrugs that will help translate the knowledge of epigenetics to improve SCLC outcomes.

The process of cancer initiation and development is a dynamic and complex mechanism involving multiple genetic and non-genetic variations. With the development of high throughput techniques like next-generation sequencing, the field of cancer biology extended beyond the protein-coding genes. It brought the functional role of noncoding RNAs into cancer-associated pathways. MicroRNAs (miRNAs) are one such class of noncoding RNAs regulating different cancer development aspects, including progression and metastasis. MicroRNA-1 (miR-1) is a highly conserved miRNA with a functional role in developing skeletal muscle precursor cells and cardiomyocytes, and acts as a consistent tumor suppressor gene. In humans, two discrete genes, MIR1–1 located on 20q13.333 and MIR1–2 located on 18q11.2 loci, encode for a single mature miR-1. Dysregulation or downregulation of miR-1 has been demonstrated in multiple cancers, including lung, breast, liver, prostate, colorectal, pancreatic, medulloblastoma, and gastric cancer. A vast number of studies have shown that miR-1 affects the multiple hallmarks of cancer like proliferation, invasion and metastasis, apoptosis, angiogenesis, chemosensitization, and immune modulation. The potential therapeutic applications of miR-1 in multiple cancer pathways provide a novel platform for developing anticancer therapies. This review focuses on the different antitumorigenic and therapeutic aspects of miR-1 including how it regulates tumor development and associated immunogenic functions.

Growth differentiation factor 15 or macrophage inhibitory cytokine-1 (GDF15/MIC-1) is a divergent member of the transforming growth factor β superfamily and has a diverse pathophysiological role in cancers, cardiometabolic disorder, and other diseases. GDF15 can control hematopoietic growth, energy homeostasis, adipose tissue metabolism, body growth, bone remodeling, and response to stress signals. The role of GDF15 in cancer development and progression is complicated and depends on the specific cancer type, stage, and tumor microenvironment. Recently, research on GDF15 and GDF15-associated signaling has accelerated due to the identification of the GDF15 receptor: glial cell line-derived neurotrophic factor (GDNF) family receptor α-like (GFRAL). Therapeutic interventions to target GDF15 and/or GFRAL revealed the mechanisms that drive its activity and might improve overall outcomes of patients with metabolic disorders or cancer. The present review highlights the structure and functions of GDF15 and its receptor, emphasizing the pleiotropic role of GDF15 in obesity, tumorigenesis, metastasis, immunomodulation, and cachexia.

Bone metastases occur in patients with advanced-stage prostate cancer (PCa). The cell-cell interaction between PCa and the bone microenvironment forms a vicious cycle that modulates the bone microenvironment, increases bone deformities, and drives tumor growth in the bone. However, the molecular mechanisms of PCa-mediated modulation of the bone microenvironment are complex and remain poorly defined. Here, we evaluated growth differentiation factor-15 (GDF15) function using in vivo preclinical PCa-bone metastasis mouse models and an in vitro bone cell coculture system. Our results suggest that PCa-secreted GDF15 promotes bone metastases and induces bone microarchitectural alterations in a preclinical xenograft model. Mechanistic studies revealed that GDF15 increases osteoblast function and facilitates the growth of PCa in bone by activating osteoclastogenesis through osteoblastic production of CCL2 and RANKL and recruitment of osteomacs. Altogether, our findings demonstrate the critical role of GDF15 in the modulation of the bone microenvironment and subsequent development of PCa bone metastasis.

Brain metastasis (BrM) is a major threat to the survival of melanoma, breast, and lung cancer patients. Circulating tumor cells (CTCs) cross the blood-brain barrier (BBB) and sustain in the brain microenvironment. Genetic mutations and epigenetic modifications have been found to be critical in controlling key aspects of cancer metastasis. Metastasizing cells confront inflammation and gradually adapt in the unique brain microenvironment. Currently, it is one of the major areas that has gained momentum. Researchers are interested in the factors that modulate neuroinflammation during BrM. We review here various epigenetic factors and mechanisms modulating neuroinflammation and how this helps CTCs to adapt and survive in the brain microenvironment. Since epigenetic changes could be modulated by targeting enzymes such as histone/DNA methyltransferase, deacetylases, acetyltransferases, and demethylases, we also summarize our current understanding of potential drugs targeting various aspects of epigenetic regulation in BrM.

Bone remodeling is a continuous and dynamic process of bone formation and resorption to maintain its integrity and homeostasis. Bone marrow is a source of various cell lineages, including osteoblasts and osteoclasts, which are involved in bone formation and resorption, respectively, to maintain bone homeostasis. Epigenetics is one of the elementary regulations governing the physiology of bone remodeling. Epigenetic modifications, mainly DNA methylation, histone modifications, and non-coding RNAs, regulate stable transcriptional programs without causing specific heritable alterations. DNA methylation in CpG-rich promoters of the gene is primarily correlated with gene silencing, and histone modifications are associated with transcriptional activation/inactivation. However, non-coding RNAs regulate the metastatic potential of cancer cells to metastasize at secondary sites. Deregulated or altered epigenetic modifications are often seen in many cancers and interwound with bone-specific tropism and cancer metastasis. Histone acetyltransferases, histone deacetylase, and DNA methyltransferases are promising targets in epigenetically altered cancer. High throughput epigenome mapping and targeting specific epigenetics modifiers will be helpful in the development of personalized epi-drugs for advanced and bone metastasis cancer patients. This review aims to discuss and gather more knowledge about different epigenetic modifications in bone remodeling and metastasis. Further, it provides new approaches for targeting epigenetic changes and therapy research.

Breast cancer (BC) is one of the most frequently diagnosed cancers in women worldwide. It has surpassed lung cancer as the leading cause of cancer-related death. Breast cancer brain metastasis (BCBM) is becoming a major clinical concern that is commonly associated with ER-ve and HER2+ve subtypes of BC patients. Metastatic lesions in the brain originate when the cancer cells detach from a primary breast tumor and establish metastatic lesions and infiltrate near and distant organs via systemic blood circulation by traversing the BBB. The colonization of BC cells in the brain involves a complex interplay in the tumor microenvironment (TME), metastatic cells, and brain cells like endothelial cells, microglia, and astrocytes. BCBM is a significant cause of morbidity and mortality and presents a challenge to developing successful cancer therapy. In this review, we discuss the molecular mechanism of BCBM and novel therapeutic strategies for patients with brain metastatic BC.

Background Small cell lung cancer (SCLC) is an aggressive lung cancer subtype that is associated with high recurrence and poor prognosis. Due to lack of potential drug targets, SCLC patients have few therapeutic options. MicroRNAs (miRNAs) provide an interesting repertoire of therapeutic molecules; however, the identification of miRNAs regulating SCLC growth and metastasis and their precise regulatory mechanisms are not well understood. Methods To identify novel miRNAs regulating SCLC, we performed miRNA-sequencing from donor/patient serum samples and analyzed the bulk RNA-sequencing data from the tumors of SCLC patients. Further, we developed a nanotechnology-based, highly sensitive method to detect microRNA-1 (miR-1, identified miRNA) in patient serum samples and SCLC cell lines. To assess the therapeutic potential of miR-1, we developed various in vitro models, including miR-1 sponge (miR-1Zip) and DOX-On-miR-1 (Tet-ON) inducible stable overexpression systems. Mouse models derived from intracardiac injection of SCLC cells (miR-1Zip and DOX-On-miR-1) were established to delineate the role of miR-1 in SCLC metastasis. In situ hybridization and immunohistochemistry were used to analyze the expression of miR-1 and target proteins (mouse and human tumor specimens), respectively. Dual-luciferase assay was used to validate the target of miR-1, and chromatin immunoprecipitation assay was used to investigate the protein-gene interactions. Results A consistent downregulation of miR-1 was observed in tumor tissues and serum samples of SCLC patients compared to their matched normal controls, and these results were recapitulated in SCLC cell lines. Gain of function studies of miR-1 in SCLC cell lines showed decreased cell growth and oncogenic signaling, whereas loss of function studies of miR-1 rescued this effect. Intracardiac injection of gain of function of miR-1 SCLC cell lines in the mouse models showed a decrease in distant organ metastasis, whereas loss of function of miR-1 potentiated growth and metastasis. Mechanistic studies revealed that CXCR4 is a direct target of miR-1 in SCLC. Using unbiased transcriptomic analysis, we identified CXCR4/FOXM1/RRM2 as a unique axis that regulates SCLC growth and metastasis. Our results further showed that FOXM1 directly binds to the RRM2 promoter and regulates its activity in SCLC. Conclusions Our findings revealed that miR-1 is a critical regulator for decreasing SCLC growth and metastasis. It targets the CXCR4/FOXM1/RRM2 axis and has a high potential for the development of novel SCLC therapies. Graphical Abstract MicroRNA-1 (miR-1) downregulation in the tumor tissues and serum samples of SCLC patients is an important hallmark of tumor growth and metastasis. The introduction of miR-1 in SCLC cell lines decreases cell growth and metastasis. Mechanistically, miR-1 directly targets CXCR4, which further prevents FOXM1 binding to the RRM2 promoter and decreases SCLC growth and metastasis.

Small cell lung cancer (SCLC) is a highly aggressive and metastatic lung cancer subtype with universal relapse and poor prognosis. The lack of potential drug targets limits targeted therapies for SCLC patients. To track down the potential therapeutic molecules in SCLC, we performed micro-RNA sequencing from the serum samples of SCLC patients and compared with the bulk RNA-sequencing data from SCLC tumor tissues. A consistent downregulation of microRNA-1 (miR-1) was observed in the SCLC patient serum samples, cell lines, and tumor tissues compared to their matched normal control. Overexpression of miR-1 in SCLC cell lines decreased cell growth and oncogenic signaling. Metastatic studies using the intracardiac injection model of SCLC cell lines showed that miR-1 overexpression decreases distant organ metastasis. Interestingly, the loss of function studies using miR-1Zip/sponging showed increased tumorigenesis and metastasis in SCLC subcutaneous and intracardiac xenografts. Mechanistic investigations revealed the CXCR4/FOXM1/RRM2 axis as a unique downstream target of miR-1 in SCLC. We found that FOXM1 transcriptionally regulates the RRM2 expression by directly binding to its promoter site, and miR-1 modulates these interactions through CXCR4. The results of the present study provided a strong preclinical rationale that miR-1 has a high potential for developing innovative SCLC therapies. Citation Format: Parvez Khan, Jawed A. Siddiqui, Shailendra Kumar Maurya, Tamara Mirzapoiazova, Prakash G. Kshirsagar, Ramakanth Chirravuri Venkata, Sanjib Chaudhary, Ranjana Kanchan, Naveenkumar Perumal, Mahek Fatima, Md Arafat Khan, Asad Ur Rehman, Imayavaramban Lakshmanan, Sidharth Mahapatra, Prakash Kulkarni, Apar Kishor Ganti, Maneesh Jain, Ravi Salgia, Surinder Kumar Batra, Mohd Wasim Nasser. MicroRNA-1 run down the growth and metastasis of small cell lung cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3760.

Medulloblastoma (MB), the most common malignant pediatric brain tumor and a leading cause of childhood mortality, is stratified into four primary subgroups, WNT (wingless), SHH (sonic hedgehog), group 3, and group 4. Patients with group 3 tumors have the poorest prognosis. Loss of 17p13.3, which houses the tumor suppressor gene miR-1253, is a frequent high-risk feature of group 3 tumors.. In this study, we show that miR-1253 levels can disrupt iron homeostasis, induce oxidative stress and lipid peroxidation, triggering an iron-mediated form of cell death called ferroptosis. In silico and in vitro analyses of group 3 tumors revealed deregulation of ABCB7, a mitochondrial iron transporter and target of miR-1253, and GPX4, a critical regulator of ferroptosis. Restoration of miR-1253 levels in group 3 cell lines resulted in downregulation of ABCB7 and GPX4, consequently increasing cytosolic and mitochondrial labile iron pools, reducing glutathione levels, in turn, resulting in mitochondrial oxidative stress and lipid peroxidation. Together, these events accelerated cancer cell death. Treating miR-1253-expressing cancer cells with cisplatin potentiated cell death by further elevating oxidative stress, depleting glutathione levels, and augmenting lipid peroxidation, with added inhibitory effects on cell viability and colony formation. Treatment with a ferroptosis inhibitor (ferrostatin-1) lead to recovery from the cytotoxic effects of this combination therapy. Together, these findings reveal a novel role for miR-1253 in enhancing ferroptosis to attenuate group 3 tumor cell growth. Our studies provide a proof-of-concept for using miR-based therapeutics to augment current chemotherapeutics in high-risk tumors. Leveraging the tumor-suppressive properties of miRNAs as adjuncts to chemotherapy may provide a promising alternative to current therapeutic strategies.

Epidemiological studies have established alcohol and smoking as independent risk factors for recurrent acute pancreatitis and chronic pancreatitis. However, the molecular players responsible for the progressive loss of pancreatic parenchyma and fibroinflammatory response are poorly characterized.Tandem mass tag-based proteomic and bioinformatics analyses were performed on the pancreata of mice exposed to alcohol, cigarette smoke, or a combination of alcohol and cigarette smoke. Biochemical, immunohistochemistry, and transcriptome analyses were performed on the pancreatic tissues and primary acinar cells treated with cerulein in combination with ethanol (50 mmol/L) and cigarette smoke extract (40 μg/mL) for the mechanistic studies.A unique alteration in the pancreatic proteome was observed in mice exposed chronically to the combination of alcohol and cigarette smoke (56.5%) compared with cigarette smoke (21%) or alcohol (17%) alone. The formation of toxic metabolites (P.001) and attenuated unfolded protein response (P.04) were the significantly altered pathways on combined exposure. The extracellular matrix (ECM) proteins showed stable malondialdehyde-acetaldehyde (MAA) adducts in the pancreata of the combination group and chronic pancreatitis patients with a history of smoking and alcohol consumption. Interestingly, MAA-ECM adducts significantly suppressed expression of X-box-binding protein-1, leading to acinar cell death in the presence of alcohol and smoking. The stable MAA-ECM adducts persist even after alcohol and smoking cessation, and significantly delay pancreatic regeneration by abrogating the expression of cyclin-dependent kinases (CDK7 and CDK5) and regeneration markers.The combined alcohol and smoking generate stable MAA-ECM adducts that increase endoplasmic reticulum stress and acinar cell death due to attenuated unfolded protein response and suppress expression of cell cycle regulators. Targeting aldehyde adducts might provide a novel therapeutic strategy for the management of recurrent acute pancreatitis and chronic pancreatitis.

Brain metastasis (BrM) is one of the leading causes of mortality in breast cancer (BC). Although BrM is associated with all BC subtypes, but it is more prevalent in triple-negative and HER2+ BC patients. Recent advancements in the multimodality treatment of primary BC have prolonged patient survival, which has in turn increased the incidence of BrM. Due to the lack of understanding of BC-BrM, there is no reliable biomarker and effective therapeutic strategy. In this regard, using publicly available databases and RNA-Seq analysis, we observed that secretory mucin MUC5AC is significantly upregulated in BC brain metastatic cell lines and tissues compared to their respective control. We validated these observations in brain-seeking BC (BSBC) cell lines and brain metastatic tissues at protein levels. Interestingly, we found that the MUC5AC levels were significantly increased in the serum of CNS metastatic patients relative to healthy donors and BC patients. Our functional studies revealed that silencing of MUC5AC in BSBC cell lines showed a significant decrease in cell adhesion, migration, brain metastatic potential, and increased survival of mice. Exploring the molecular mechanism further revealed that MUC5AC interacts with CD44v6 and c-Met and deletion of MUC5AC demonstrated a decrease in the expression of c-MET and CD44v6. Furthermore, pharmacological targeting of MUC5AC through c-Met inhibitor reduces the expression of CD44v6 and MUC5AC, suggesting that c-Met inhibitors could be used as a novel therapeutics for targeting MUC5AC and thereby attenuating BC brain metastasis. Altogether, our study demonstrates that MUC5AC/CD44v6/c-Met axis could be used as a novel approach to prevent breast cancer brain metastasis. Citation Format: Shailendra Kumar Maurya, Jawed A. Siddiqui, Shailendra K. Gautama, Ranjana K. Kanchan, Ramesh Pothuraju, Gopalakrishnan Natarajan, Pranita Atri, Ramakanth C. Venkata, Rakesh Bhatia, Parvez Khan, Asad Ur Rehmana, Sanjib Chaudhary, Naveenkumar Perumal, Sidharth Mahapatra, Hitendra S. Chand, Maneesh Jain, Juan A. Santamaria-Barriab, Diana M. Cittelly, Surinder K. Batra, Mohd W. Nasser. A novel role of MUC5AC/CD44v6/c-Met axis in breast cancer brain metastasis [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 2431.