Medical Biochemistry Commons^™

Molecular And Metabolic Regulation Of Immunosuppression In Metastatic Pancreatic Ductal Adenocarcinoma, Shailendra K. Gautam, Surinder K. Batra, Maneesh Jain

Journal Articles: Biochemistry & Molecular Biology

Immunosuppression is a hallmark of pancreatic ductal adenocarcinoma (PDAC), contributing to early metastasis and poor patient survival. Compared to the localized tumors, current standard-of-care therapies have failed to improve the survival of patients with metastatic PDAC, that necessecitates exploration of novel therapeutic approaches. While immunotherapies such as immune checkpoint blockade (ICB) and therapeutic vaccines have emerged as promising treatment modalities in certain cancers, limited responses have been achieved in PDAC. Therefore, specific mechanisms regulating the poor response to immunotherapy must be explored. The immunosuppressive microenvironment driven by oncogenic mutations, tumor secretome, non-coding RNAs, and tumor microbiome persists throughout PDAC progression, …

Chimeric Antibody Targeting Unique Epitope On Onco-Mucin16 Reduces Tumor Burden In Pancreatic And Lung Malignancies, Ashu Shah, Sanjib Chaudhary, Imayavaramban Lakshmanan, Abhijit Aithal, Sophia G. Kisling, Claire Sorrell, Saravanakumar Marimuthu, Shailendra K. Gautam, Sanchita Rauth, Prakash Kshirsagar, Jesse L. Cox, Gopalakrishnan Natarajan, Rakesh Bhatia, Kavita Mallya, Satyanarayana Rachagani, Mohd W. Nasser, Apar Kishor Ganti, Ravi Salgia, Sushil Kumar, Maneesh Jain, Moorthy P. Ponnusamy, Surinder K. Batra

Journal Articles: Biochemistry & Molecular Biology

Aberrantly expressed onco-mucin 16 (MUC16) and its post-cleavage generated surface tethered carboxy-terminal (MUC16-Cter) domain are strongly associated with poor prognosis and lethality of pancreatic (PC) and non-small cell lung cancer (NSCLC). To date, most anti-MUC16 antibodies are directed towards the extracellular domain of MUC16 (CA125), which is usually cleaved and shed in the circulation hence obscuring antibody accessibility to the cancer cells. Herein, we establish the utility of targeting a post-cleavage generated, surface-tethered oncogenic MUC16 carboxy-terminal (MUC16-Cter) domain by using a novel chimeric antibody in human IgG1 format, ch5E6, whose epitope expression directly correlates with disease severity in both cancers. …

Red Cabbage Juice-Mediated Gut Microbiota Modulation Improves Intestinal Epithelial Homeostasis And Ameliorates Colitis, Emily Jean Wilson, Nagabhishek Sirpu Natesh, Parsa Ghadermazi, Ramesh Pothuraju, Dipakkumar R. Prajapati, Sanjit Pandey, Jussuf T. Kaifi, John R. Dodam, Jeffrey N. Bryan, Christian L. Lorson, Aude A. Watrelot, Jason M. Foster, Thomas J. Mansell, Siu Hung Joshua Chan, Surinder K. Batra, Jeyamkondan Subbiah, Satyanarayana Rachagani

Journal Articles: Biochemistry & Molecular Biology

Gut microbiota plays a crucial role in inflammatory bowel diseases (IBD) and can potentially prevent IBD through microbial-derived metabolites, making it a promising therapeutic avenue. Recent evidence suggests that despite an unclear underlying mechanism, red cabbage juice (RCJ) alleviates Dextran Sodium Sulfate (DSS)-induced colitis in mice. Thus, the study aims to unravel the molecular mechanism by which RCJ modulates the gut microbiota to alleviate DSS-induced colitis in mice. Using C57BL/6J mice, we evaluated RCJ's protective role in DSS-induced colitis through two cycles of 3% DSS. Mice were daily gavaged with PBS or RCJ until the endpoint, and gut microbiota composition …

Gdf15 Promotes Prostate Cancer Bone Metastasis And Colonization Through Osteoblastic Ccl2 And Rankl Activation, Jawed A. Siddiqui, Parthasarathy Seshacharyulu, Sakthivel Muniyan, Ramesh Pothuraju, Parvez Khan, Raghupathy Vengoji, Sanjib Chaudhary, Shailendra K. Maurya, Subodh M. Lele, Maneesh Jain, K Datta, Mohd W. Nasser, Surinder K. Batra

Journal Articles: Biochemistry & Molecular Biology

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 …

Liquid Biopsy: A Step Closer To Transform Diagnosis, Prognosis And Future Of Cancer Treatments, Saife N. Lone, Sabah Nisar, Tariq Masoodi, Mayank Singh, Arshi Rizwan, Sheema Hashem, Wael El-Rifai, Davide Bedognetti, Surinder K. Batra, Mohammad Haris, Ajaz A. Bhat, Muzafar A. Macha

Journal Articles: Biochemistry & Molecular Biology

Over the past decade, invasive techniques for diagnosing and monitoring cancers are slowly being replaced by non-invasive methods such as liquid biopsy. Liquid biopsies have drastically revolutionized the field of clinical oncology, offering ease in tumor sampling, continuous monitoring by repeated sampling, devising personalized therapeutic regimens, and screening for therapeutic resistance. Liquid biopsies consist of isolating tumor-derived entities like circulating tumor cells, circulating tumor DNA, tumor extracellular vesicles, etc., present in the body fluids of patients with cancer, followed by an analysis of genomic and proteomic data contained within them. Methods for isolation and analysis of liquid biopsies have rapidly …

Liquid Biopsies To Occult Brain Metastasis, Asad Ur Rehman, Parvez Khan, Shailendra K. Maurya, Jawed A. Siddiqui, Juan A. Santamaria-Barria, Surinder K. Batra, Mohd W. Nasser

Journal Articles: Biochemistry & Molecular Biology

Brain metastasis (BrM) is a major problem associated with cancer-related mortality, and currently, no specific biomarkers are available in clinical settings for early detection. Liquid biopsy is widely accepted as a non-invasive method for diagnosing cancer and other diseases. We have reviewed the evidence that shows how the molecular alterations are involved in BrM, majorly from breast cancer (BC), lung cancer (LC), and melanoma, with an inception in how they can be employed for biomarker development. We discussed genetic and epigenetic changes that influence cancer cells to breach the blood-brain barrier (BBB) and help to establish metastatic lesions in the …

Depletion Of Transmembrane Mucin 4 (Muc4) Alters Intestinal Homeostasis In A Genetically Engineered Mouse Model Of Colorectal Cancer, Ramesh Pothuraju, Priya Pai, Sanjib Chaudhary, Jawed A. Siddiqui, Jesse L. Cox, Sukhwinder Kaur, Satyanarayana Rachagani, Hemant K. Roy, Michael Bouvet, Surinder K. Batra

Journal Articles: Biochemistry & Molecular Biology

Mucins are components of the mucus layer overlying the intestinal epithelial cells, which maintains physiological homeostasis. Altered mucin expression is associated with disease progression. Expression of MUC4 decreases in colorectal cancer (CRC); however, its functional role and implications in the intestinal pathology in CRC are not studied well. Therefore, we generated a genetically engineered Muc4 knockout (Muc4^-/-) CRC mouse model by crossing with Muc4^-/- and Apc^flox/flox mice in the presence of colon-specific inducible Cre. We observed that deficiency of Muc4 results in an increased number of macroscopic tumors in the colon and rectal region and leads …

Ubiquitous Aberration In Cholesterol Metabolism Across Pancreatic Ductal Adenocarcinoma, Venugopal Gunda, Thiago C. Genaro-Mattos, Jyoti B. Kaushal, Ramakanth C. Venkata, Gopalakrishnan Natarajan, Kavita Mallya, Paul M. Grandgenett, Karoly Mirnics, Surinder K. Batra, Zeljka Korade, Satyanarayana Rachagani

Journal Articles: Biochemistry & Molecular Biology

Pancreatic cancer (PC) is characterized by metabolic deregulations that often manifest as deviations in metabolite levels and aberrations in their corresponding metabolic genes across the clinical specimens and preclinical PC models. Cholesterol is one of the critical metabolites supporting PC, synthesized or acquired by PC cells. Nevertheless, the significance of the de novo cholesterol synthesis pathway has been controversial in PC, indicating the need to reassess this pathway in PC. We utilized preclinical models and clinical specimens of PC patients and cell lines and utilized mass spectrometry-based sterol analysis. Further, we also performed in silico analysis to corroborate the significance …

The Gsk3 Kinase And Lztr1 Protein Regulate The Stability Of Ras Family Proteins And The Proliferation Of Pancreatic Cancer Cells, Chitra Palanivel, Neha Chaudhary, Parthasarathy Seshacharyulu, Jesse L. Cox, Ying Yan, Surinder K. Batra, Michel M. Ouellette

Journal Articles: Biochemistry & Molecular Biology

Ras family proteins are membrane-bound GTPases that control proliferation, survival, and motility. Many forms of cancers are driven by the acquisition of somatic mutations in a RAS gene. In pancreatic cancer (PC), more than 90% of tumors carry an activating mutation in KRAS. Mutations in components of the Ras signaling pathway can also be the cause of RASopathies, a group of developmental disorders. In a subset of RASopathies, the causal mutations are in the LZTR1 protein, a substrate adaptor for E3 ubiquitin ligases that promote the degradation of Ras proteins. Here, we show that the function of LZTR1 is regulated …

Tumor Microenvironment Enriches The Stemness Features: The Architectural Event Of Therapy Resistance And Metastasis, Palanisamy Nallasamy, Rama Krishna Nimmakayala, Seema Parte, Abhirup C. Are, Surinder K. Batra, Moorthy P. Ponnusamy

Journal Articles: Biochemistry & Molecular Biology

Cancer divergence has many facets other than being considered a genetic term. It is a tremendous challenge to understand the metastasis and therapy response in cancer biology; however, it postulates the opportunity to explore the possible mechanism in the surrounding tumor environment. Most deadly solid malignancies are distinctly characterized by their tumor microenvironment (TME). TME consists of stromal components such as immune, inflammatory, endothelial, adipocytes, and fibroblast cells. Cancer stem cells (CSCs) or cancer stem-like cells are a small sub-set of the population within cancer cells believed to be a responsible player in the self-renewal, metastasis, and therapy response of …

Multifunctionality Of Prostatic Acid Phosphatase In Prostate Cancer Pathogenesis, Evgenia Alpert, Armin Akhavan, Arie Gruzman, William J. Hansen, Joshua Lehrer-Graiwer, Steven C. Hall, Eric Johansen, Sean Mcallister, Mittul Gulati, Ming-Fong Lin, Vishwanath R Lingappa

Journal Articles: Biochemistry & Molecular Biology

The role of human prostatic acid phosphatase (PAcP, P15309|PPAP_HUMAN) in prostate cancer was investigated using a new proteomics tool termed signal sequence swapping (replacement of domains from the native cleaved amino terminal signal sequence of secretory/membrane proteins with corresponding regions of functionally distinct signal sequence subtypes). This manipulation preferentially redirects proteins to different pathways of biogenesis at the endoplasmic reticulum (ER), magnifying normally difficult to detect subsets of the protein of interest. For PAcP, this technique reveals three forms identical in amino acid sequence but profoundly different in physiological functions, subcellular location, and biochemical properties. These three forms of PAcP …

Androgen Receptor, Although Not A Specific Marker For, Is A Novel Target To Suppress Glioma Stem Cells As A Therapeutic Strategy For Glioblastoma, Nan Zhao, Fei Wang, Shaheen Ahmed, Kan Liu, Chi Zhang, Sahara J. Cathcart, Dominick J. Dimaio, Michael Punsoni, Bingjie Guan, Ping Zhou, Shuo Wang, Surinder K. Batra, Tatiana K. Bronich, Tom K. Hei, Chi Lin, Chi Zhang

Journal Articles: Biochemistry & Molecular Biology

Targeting androgen receptor (AR) has been shown to be promising in treating glioblastoma (GBM) in cell culture and flank implant models but the mechanisms remain unclear. AR antagonists including enzalutamide are available for treating prostate cancer patients in clinic and can pass the blood-brain barrier, thus are potentially good candidates for GBM treatment but have not been tested in GBM orthotopically. Our current studies confirmed that in patients, a majority of GBM tumors overexpress AR in both genders. Enzalutamide inhibited the proliferation of GBM cells both in vitro and in vivo. Although confocal microscopy demonstrated that AR is expressed …

Tumor- And Osteoclast-Derived Nrp2 In Prostate Cancer Bone Metastases, Navatha S. Polavaram, Samikshan Dutta, Ridwan Islam, Arup K. Bag, Sohini Roy, David Poitz, Jeffrey Karnes, Lorenz C. Hofbauer, Manish Kohli, Brian A. Costello, Raffael Jimenez, Surinder K. Batra, Benjamin A. Teply, Michael H. Muders, K Datta

Journal Articles: Biochemistry & Molecular Biology

Understanding the role of neuropilin 2 (NRP2) in prostate cancer cells as well as in the bone microenvironment is pivotal in the development of an effective targeted therapy for the treatment of prostate cancer bone metastasis. We observed a significant upregulation of NRP2 in prostate cancer cells metastasized to bone. Here, we report that targeting NRP2 in cancer cells can enhance taxane-based chemotherapy with a better therapeutic outcome in bone metastasis, implicating NRP2 as a promising therapeutic target. Since, osteoclasts present in the tumor microenvironment express NRP2, we have investigated the potential effect of targeting NRP2 in osteoclasts. Our results …

St6galnac-I Promotes Lung Cancer Metastasis By Altering Muc5ac Sialylation, Imayavaramban Lakshmanan, Sanjib Chaudhary, Raghupathy Vengoji, Parthasarathy Seshacharyulu, Satyanarayana Rachagani, Joseph Carmicheal, Rahat Jahan, Pranita Atri, Ramakanth C. Venkata, Rohitesh Gupta, Saravanakumar Marimuthu, Naveenkumar Perumal, Sanchita Rauth, Sukhwinder Kaur, Kavita Mallya, Lynette M. Smith, Subodh M. Lele, Moorthy P. Ponnusamy, Mohd W. Nasser, Ravi Salgia, Surinder K. Batra, Apar Kishor Ganti

Journal Articles: Biochemistry & Molecular Biology

Lung cancer (LC) is the leading cause of cancer-related mortality. However, the molecular mechanisms associated with the development of metastasis is poorly understood. Understanding the biology of LC metastasis is critical to unveil the molecular mechanisms for designing targeted therapies. We developed two genetically engineered LC mouse models- Kras^G12D ;Trp53^R172H/+ ;Ad-Cre (KPA) and Kras^G12D ; Ad-Cre (KA). Survival analysis showed significantly (P=0.0049) shorter survival in KPA tumor-bearing mice as compared to KA, suggesting the aggressiveness of the model. Our transcriptomic data showed high expression of St6galnac-I in KPA compared to KA tumors. ST6GalNAc-I is an O-glycosyltransferase, which …

Amyloid Precursor-Like Protein 2 Expression Increases During Pancreatic Cancer Development And Shortens The Survival Of A Spontaneous Mouse Model Of Pancreatic Cancer., Brittany J. Poelaert, Shelby M. Knoche, Alaina C. Larson, Poomy Pandey, Parthasarathy Seshacharyulu, Nuzhat Khan, H. Carlo Maurer, Kenneth P. Olive, Yuri Sheinin, Rizwan Ahmad, Amar B. Singh, Surinder K. Batra, Satyanarayana Rachagani, Joyce C. Solheim

Journal Articles: Biochemistry & Molecular Biology

In the United States, pancreatic cancer is a major cause of cancer-related deaths. Although substantial efforts have been made to understand pancreatic cancer biology and improve therapeutic efficacy, patients still face a bleak chance of survival. A greater understanding of pancreatic cancer development and the identification of novel treatment targets are desperately needed. Our analysis of gene expression data from patient samples showed an increase in amyloid precursor-like protein 2 (APLP2) expression within primary tumor epithelium relative to pancreatic intraepithelial neoplasia (PanIN) epithelial cells. Augmented expression of APLP2 in primary tumors compared to adjacent stroma was also observed. Genetically engineered …

Rna-Based Therapies: A Cog In The Wheel Of Lung Cancer Defense, Parvez Khan, Jawed A. Siddiqui, Imayavaramban Lakshmanan, Apar Kishor Ganti, Ravi Salgia, Maneesh Jain, Surinder K. Batra, Mohd W. Nasser

Journal Articles: Biochemistry & Molecular Biology

Lung cancer (LC) is a heterogeneous disease consisting mainly of two subtypes, non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), and remains the leading cause of death worldwide. Despite recent advances in therapies, the overall 5-year survival rate of LC remains less than 20%. The efficacy of current therapeutic approaches is compromised by inherent or acquired drug-resistance and severe off-target effects. Therefore, the identification and development of innovative and effective therapeutic approaches are critically desired for LC. The development of RNA-mediated gene inhibition technologies was a turning point in the field of RNA biology. The critical regulatory …

Tumor Microenvironment: An Evil Nexus Promoting Aggressive Head And Neck Squamous Cell Carcinoma And Avenue For Targeted Therapy, Ajaz A. Bhat, Parvaiz Yousuf, Nissar A. Wani, Arshi Rizwan, Shyam S. Chauhan, Mushtaq A. Siddiqi, Davide Bedognetti, Wael El-Rifai, Michael P. Frenneaux, Surinder K. Batra, Mohammad Haris, Muzafar A. Macha

Journal Articles: Biochemistry & Molecular Biology

Head and neck squamous cell carcinoma (HNSCC) is a very aggressive disease with a poor prognosis for advanced-stage tumors. Recent clinical, genomic, and cellular studies have revealed the highly heterogeneous and immunosuppressive nature of HNSCC. Despite significant advances in multimodal therapeutic interventions, failure to cure and recurrence are common and account for most deaths. It is becoming increasingly apparent that tumor microenvironment (TME) plays a critical role in HNSCC tumorigenesis, promotes the evolution of aggressive tumors and resistance to therapy, and thereby adversely affects the prognosis. A complete understanding of the TME factors, together with the highly complex tumor-stromal interactions, …

Mir-212-3p Functions As A Tumor Suppressor Gene In Group 3 Medulloblastoma Via Targeting Nuclear Factor I/B (Nfib), Naveenkumar Perumal, Ranjana K. Kanchan, David Doss, Noah Bastola, Pranita Atri, Ramakanth C. Venkata, Ishwor Thapa, Raghupathy Vengoji, Shailendra K. Maurya, David Klinkebiel, Geoffrey A. Talmon, Mohd W. Nasser, Surinder K. Batra, Sidharth Mahapatra

Journal Articles: Biochemistry & Molecular Biology

Haploinsufficiency of chromosome 17p and c-Myc amplification distinguish group 3 medulloblastomas which are associated with early metastasis, rapid recurrence, and swift mortality. Tumor suppressor genes on this locus have not been adequately characterized. We elucidated the role of miR-212-3p in the pathophysiology of group 3 tumors. First, we learned that miR-212-3p undergoes epigenetic silencing by histone modifications in group 3 tumors. Restoring its expression reduced cancer cell proliferation, migration, colony formation, and wound healing in vitro and attenuated tumor burden and improved survival in vivo. MiR-212-3p also triggered c-Myc destabilization and degradation, leading to elevated apoptosis. We then isolated an …

Differential Gene Expression-Based Connectivity Mapping Identified Novel Drug Candidate And Improved Temozolomide Efficacy For Glioblastoma, Raghupathy Vengoji, Pranita Atri, Muzafar A. Macha, Parthasarathy Seshacharyulu, Naveenkumar Perumal, Kavita Mallya, Yutong Liu, Lynette M. Smith, Satyanarayana Rachagani, Sidharth Mahapatra, Moorthy P. Ponnusamy, Maneesh Jain, Surinder K. Batra, Nicole Shonka

Journal Articles: Biochemistry & Molecular Biology

BACKGROUND: Glioblastoma (GBM) has a devastating median survival of only one year. Treatment includes resection, radiation therapy, and temozolomide (TMZ); however, the latter increased median survival by only 2.5 months in the pivotal study. A desperate need remains to find an effective treatment.

METHODS: We used the Connectivity Map (CMap) bioinformatic tool to identify candidates for repurposing based on GBM's specific genetic profile. CMap identified histone deacetylase (HDAC) inhibitors as top candidates. In addition, Gene Expression Profiling Interactive Analysis (GEPIA) identified HDAC1 and HDAC2 as the most upregulated and HDAC11 as the most downregulated HDACs. We selected PCI-24781/abexinostat due to …

The Current Landscape Of Antibody-Based Therapies In Solid Malignancies, Ashu Shah, Sanchita Rauth, Abhijit Aithal, Sukhwinder Kaur, Koelina Ganguly, Catherine Orzechowski, Grish C. Varshney, Maneesh Jain, Surinder K. Batra

Journal Articles: Biochemistry & Molecular Biology

Over the past three decades, monoclonal antibodies (mAbs) have revolutionized the landscape of cancer therapy. Still, this benefit remains restricted to a small proportion of patients due to moderate response rates and resistance emergence. The field has started to embrace better mAb-based formats with advancements in molecular and protein engineering technologies. The development of a therapeutic mAb with long-lasting clinical impact demands a prodigious understanding of target antigen, effective mechanism of action, gene engineering technologies, complex interplay between tumor and host immune system, and biomarkers for prediction of clinical response. This review discusses the various approaches used by mAbs for …

Repurposing Niclosamide For Targeting Pancreatic Cancer By Inhibiting Hh/Gli Non-Canonical Axis Of Gsk3Β, Jyoti B. Kaushal, Rakesh Bhatia, Ranjana K. Kanchan, Pratima Raut, Surya Mallapragada, Quan P. Ly, Surinder K. Batra, Satyanarayana Rachagani

Journal Articles: Biochemistry & Molecular Biology

Niclosamide (Nic), an FDA-approved anthelmintic drug, is reported to have anti-cancer efficacy and is being assessed in clinical trials for various solid tumors. Based on its ability to target multiple signaling pathways, in the present study, we evaluated the therapeutic efficacy of Nic on pancreatic cancer (PC) in vitro. We observed an anti-cancerous effect of this drug as shown by the G0/G1 phase cell cycle arrest, inhibition of PC cell viability, colony formation, and migration. Our results revealed the involvement of mitochondrial stress and mTORC1-dependent autophagy as the predominant players of Nic-induced PC cell death. Significant reduction of Nic-induced reactive …

Emerging Role Of Mir-345 And Its Effective Delivery As A Potential Therapeutic Candidate In Pancreatic Cancer And Other Cancers, Nagabhishek Sirpu Natesh, Brianna M. White, Maia M. C. White, Metin Uz, Rakhee Rathnam Kalari Kandy, Surinder K. Batra, Surya K. Mallapragada, Satyanarayana Rachagani

Journal Articles: Biochemistry & Molecular Biology

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with high mortality, poor prognosis, and palliative treatments, due to the rapid upregulation of alternative compensatory pathways and desmoplastic reaction. miRNAs, small non-coding RNAs, have been recently identified as key players regulating cancer pathogenesis. Dysregulated miRNAs are associated with molecular pathways involved in tumor development, metastasis, and chemoresistance in PDAC, as well as other cancers. Targeted treatment strategies that alter miRNA levels in cancers have promising potential as therapeutic interventions. miRNA-345 (miR-345) plays a critical role in tumor suppression and is differentially expressed in various cancers, including pancreatic cancer (PC). The underlying …

Dynamic Phenotypic Switching And Group Behavior Help Non-Small Cell Lung Cancer Cells Evade Chemotherapy, Arin Nam, Atish Mohanty, Supriyo Bhattacharya, Sourabh Kotnala, Srisairam Achuthan, Kishore Hari, Saumya Srivastava, Linlin Guo, Anusha Nathan, Rishov Chatterjee, Maneesh Jain, Mohd W. Nasser, Surinder K. Batra, Govindan Rangarajan, Erminia Massarelli, Herbert Levine, Mohit Kumar Jolly, Prakash Kulkarni, Ravi Salgia

Journal Articles: Biochemistry & Molecular Biology

Drug resistance, a major challenge in cancer therapy, is typically attributed to mutations and genetic heterogeneity. Emerging evidence suggests that dynamic cellular interactions and group behavior also contribute to drug resistance. However, the underlying mechanisms remain poorly understood. Here, we present a new mathematical approach with game theoretical underpinnings that we developed to model real-time growth data of non-small cell lung cancer (NSCLC) cells and discern patterns in response to treatment with cisplatin. We show that the cisplatin-sensitive and cisplatin-tolerant NSCLC cells, when co-cultured in the absence or presence of the drug, display dynamic group behavior strategies. Tolerant cells exhibit …

Evaluation Of Somatic Mutations In Solid Metastatic Pan-Cancer Patients, Moom R. Roosan, Isa Mambetsariev, Rebecca Pharaon, Jeremy Fricke, Angel R. Baroz, Joseph Chao, Chen Chen, Mohd W. Nasser, Ramakanth C. Venkata, Maneesh Jain, Lynette M. Smith, Susan E. Yost, Karen L. Reckamp, Raju Pillai, Leonidas Arvanitis, Michelle Afkhami, Edward W. Wang, Vincent Chung, Mihaela Cristea, Marwan Fakih, Marianna Koczywas, Erminia Massarelli, Joanne Mortimer, Yuan Yuan, Surinder K. Batra, Sumanta Pal, Ravi Salgia

Journal Articles: Biochemistry & Molecular Biology

Metastasis continues to be the primary cause of all cancer-related deaths despite the recent advancements in cancer treatments. To evaluate the role of mutations in overall survival (OS) and treatment outcomes, we analyzed 957 metastatic patients with seven major cancer types who had available molecular testing results with a FoundationOne CDx^® panel. The most prevalent genes with somatic mutations were TP53, KRAS, APC, and LRP1B. In this analysis, these genes had mutation frequencies higher than in publicly available datasets. We identified that the somatic mutations were seven mutually exclusive gene pairs and an additional fifty-two co-occurring gene pairs. Mutations …

Disruption Of Fdps/Rac1 Axis Radiosensitizes Pancreatic Ductal Adenocarcinoma By Attenuating Dna Damage Response And Immunosuppressive Signalling, Parthasarathy Seshacharyulu, Sushanta Halder, Rama Krishna Nimmakayala, Satyanarayana Rachagani, Sanjib Chaudhary, Pranita Atri, Ramakanth C. Venkata, Michel M. Ouellette, Joseph Carmicheal, Shailendra K. Gautam, Raghupathy Vengoji, Shuo Wang, Sicong Li, Lynette M. Smith, Geoffrey A. Talmon, Kelsey Klute, Quan P. Ly, Bradley N. Reames, Jean L. Grem, Lyudmyla Berim, James C. Padussis, Sukhwinder Kaur, Sushil Kumar, Moorthy P. Ponnusamy, Maneesh Jain, Chi Lin, Surinder K. Batra

Journal Articles: Biochemistry & Molecular Biology

BACKGROUND: Radiation therapy (RT) has a suboptimal effect in patients with pancreatic ductal adenocarcinoma (PDAC) due to intrinsic and acquired radioresistance (RR). Comprehensive bioinformatics and microarray analysis revealed that cholesterol biosynthesis (CBS) is involved in the RR of PDAC. We now tested the inhibition of the CBS pathway enzyme, farnesyl diphosphate synthase (FDPS), by zoledronic acid (Zol) to enhance radiation and activate immune cells.

METHODS: We investigated the role of FDPS in PDAC RR using the following methods: in vitro cell-based assay, immunohistochemistry, immunofluorescence, immunoblot, cell-based cholesterol assay, RNA sequencing, tumouroids (KPC-murine and PDAC patient-derived), orthotopic models, and PDAC patient's …

Blocking C-Met/Erbb1 Axis Prevents Brain Metastasis In Erbb2+ Breast Cancer, Shailendra K. Gautam, Ranjana K. Kanchan, Jawed A. Siddiqui, Shailendra K. Maurya, Sanchita Rauth, Naveenkumar Perumal, Pranita Atri, Ramakanth C. Venkata, Kavita Mallya, Sameer Mirza, Moorthy P. Ponnusamy, Vimla Band, Sidharth Mahapatra, Maneesh Jain, Surinder K. Batra, Mohd W. Nasser

Journal Articles: Biochemistry & Molecular Biology

Brain metastasis (BrM) remains a significant cause of cancer-related mortality in epidermal growth factor receptor 2-positive (ERBB2⁺) breast cancer (BC) patients. We proposed here that a combination treatment of irreversible tyrosine kinase inhibitor neratinib (NER) and the c-MET inhibitor cabozantinib (CBZ) could prevent brain metastasis. To address this, we first tested the combination treatment of NER and CBZ in the brain-seeking ERBB2⁺ cell lines SKBrM3 and JIMT-1-BR3, and in ERBB2⁺ organoids that expressed the c-MET/ERBB1 axis. Next, we developed and characterized an orthotopic mouse model of spontaneous BrM and evaluated the therapeutic effect of CBZ and …

Acinar Transformed Ductal Cells Exhibit Differential Mucin Expression In A Tamoxifen-Induced Pancreatic Ductal Adenocarcinoma Mouse Model, Kavita Mallya, Dhanya Haridas, Parthasarathy Seshacharyulu, Ramesh Pothuraju, Wade M. Junker, Shiv Ram Krishn, Sakthivel Muniyan, Raghupathy Vengoji, Surinder K. Batra, Satyanarayana Rachagani

Journal Articles: Biochemistry & Molecular Biology

Pancreatic cancer (PC) is acquired postnatally; to mimic this scenario, we developed an inducible Kras^G12D; Ptf1a-CreER™ (iKC) mouse model, in which Kras is activated postnatally at week 16 upon tamoxifen (TAM) administration. Upon TAM treatment, iKC mice develop pancreatic intraepithelial neoplasia (PanIN) lesions and PC with metastasis at the fourth and fortieth weeks, respectively, and exhibited acinar-to-ductal metaplasia (ADM) and transdifferentiation. Kras activation upregulated the transcription factors Ncoa3, p-cJun and FoxM1, which in turn upregulated expression of transmembrane mucins (Muc1, Muc4 and Muc16) and secretory mucin (Muc5Ac). Interestingly, knockdown of Kras^G12D in multiple PC cell lines resulted …

Alcohol And Smoking Mediated Modulations In Adaptive Immunity In Pancreatitis, Rakesh Bhatia, Christopher Thompson, Koelina Ganguly, Shailender K. Singh, Surinder K. Batra, Sushil Kumar

Journal Articles: Biochemistry & Molecular Biology

Pancreatitis is a condition of pancreatic inflammation driven by injury to the pancreatic parenchyma. The extent of acinar insult, intensity, and type of immune response determines the severity of the disease. Smoking, alcohol and autoimmune pancreatitis are some of the predominant risk factors that increase the risk of pancreatitis by differentially influencing the adaptive immune system. The overall decrease in peripheral lymphocyte (T-, B- and (natural killer T-) NKT-cell) count and increased infiltration into the damaged pancreatic tissue highlight the contribution of adaptive immunity in the disease pathology. Smoking and alcohol modulate the responsiveness and apoptosis of T- and B-cells …

Molecular Mechanisms Of Manganese Porphyrin Compounds In The Prevention Of Radiation-Induced Fibrosis, Shashank Shrishrimal

Theses & Dissertations

Radiation therapy is frequently used as a treatment strategy for prostate cancer patients, which leads to several side effects due to damage to health tissue around the tumor and the development of radiation-induced fibrosis (RIF). Manganese (III) meso-tetrakis (N-ethylpyridinium-2-yl) porphyrin (MnTE-2-PyP or T2E or BMX-010) and other similar manganese porphyrin compounds that scavenge superoxide molecules have been demonstrated to be effective radioprotectors and prevent the development of RIF. However, understanding of the radioprotective molecular pathway associated with these compounds remains limited. Recent RNA-sequencing data from our laboratory revealed that MnTE-2-PyP treatment may activate the nuclear factor erythroid 2-related factor 2 …

Differentiating Peripherally-Located Small Cell Lung Cancer From Non-Small Cell Lung Cancer Using A Ct Radiomic Approach, Bihong T. Chen, Zikuan Chen, Ningrong Ye, Isa Mambetsariev, Jeremy Fricke, Ebenezer Daniel, George Wang, Chi Wah Wong, Russell C. Rockne, Rivka R. Colen, Mohd W. Nasser, Surinder K. Batra, Andrei I. Holodny, Sagus Sampath, Ravi Salgia

Journal Articles: Biochemistry & Molecular Biology

Lung cancer can be classified into two main categories: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), which are different in treatment strategy and survival probability. The lung CT images of SCLC and NSCLC are similar such that their subtle differences are hardly visually discernible by the human eye through conventional imaging evaluation. We hypothesize that SCLC/NSCLC differentiation could be achieved via computerized image feature analysis and classification in feature space, as termed a radiomic model. The purpose of this study was to use CT radiomics to differentiate SCLC from NSCLC adenocarcinoma. Patients with primary lung cancer, …