MUC16 is overexpressed in multiple cancers and plays an important role in tumorigenicity and acquired resistance to therapy. Area covered: In this review, we describe the role of MUC16 under normal physiological conditions and during tumorigenesis. First, we provide a summary of research on MUC16 from its discovery as CA125 to present anti-MUC16 therapy trials that are currently in the initial phases of clinical testing. Finally, we discuss the reasons for the limited effectiveness of these therapies and discuss the direction and focus of future research. Expert opinion: Apart from its protective role in normal physiology, MUC16 contributes to disease progression and metastasis in several malignancies. Due to its aberrant overexpression, it is a promising target for diagnosis and therapy. Cleavage and shedding of its extracellular domain is the major barrier for efficient targeting of MUC16-expressing cancers. Concerted efforts should be undertaken to target the noncleaved cell surface retained portion of MUC16. Such efforts should be accompanied by basic research to understand MUC16 cleavage and decipher the functioning of MUC16 cytoplasmic tail. While previous efforts to activate anti-MUC16 immune response using anti-CA125 idiotype antibodies have met with limited success, ideification of neo-antigenic epitopes in MUC16 that correlate with improved survival have raised raised hopes for developing MUC16-targeted immunotherapy.

Secreted mucin 5AC (MUC5AC) is the most abundantly overexpressed member of the mucin family during early pancreatic intraepithelial neoplasia stage I (PanIN-I) of pancreatic cancer. To comprehend the contribution of Muc5ac in pancreatic cancer pathology, we genetically ablated it in an autochthonous murine model (KrasG12D; Pdx-1cre, KC), which mirrors the early stages of pancreatic cancer development. Neoplastic onset and the PanIN lesion progression were significantly delayed in Muc5ac knockout (KrasG12D; Pdx-1 cre; Muc5ac−/−, KCM) animals with a 50% reduction in PanIN-2 and 70% reduction in PanIN-3 lesions compared with KC at 50 weeks of age. High-throughput RNA-sequencing analysis from pancreatic tissues of KCM animals revealed a significant decrease in cancer stem cell (CSC) markers Aldh1a1, Klf4, EpCAM, and CD133. Furthermore, the silencing of MUC5AC in human pancreatic cancer cells reduced their tumorigenic propensity, as indicated by a significant decline in tumor formation frequency by limiting dilution assay upon subcutaneous administration. The contribution of MUC5AC in CSC maintenance was corroborated by a significant decrease in tumor burden upon orthotopic implantation of MUC5AC-depleted pancreatic cancer cells. Mechanistically, MUC5AC potentiated oncogenic signaling through integrin αvβ5, pSrc (Y416), and pSTAT3 (Y705). Phosphorylated STAT3, in turn, upregulated Klf4 expression, thereby enriching the self-renewing CSC population. A strong positive correlation of Muc5ac with Klf4 and pSTAT3 in the PanIN lesions of KC mouse pancreas reinforces the crucial involvement of MUC5AC in bolstering the CSC-associated tumorigenic properties of Kras-induced metaplastic cells, which leads to pancreatic cancer onset and progression. Significance: This study elucidates that de novo expression of MUC5AC promotes cancer cell stemness during Kras-driven pancreatic tumorigenesis and can be targeted for development of a novel therapeutic regimen.

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 tumor targeting and mechanisms of therapeutic resistance that is not only caused by the heterogeneity of tumor antigen, but also the resistance imposed by tumor microenvironment (TME), including inefficient delivery to the tumor, alteration of effector functions in the TME, and Fc-gamma receptor expression diversity and polymorphism. Further, this article provides a perspective on potential strategies to overcome these barriers and how diagnostic and prognostic biomarkers are being used in predicting response to mAb-based therapies. Overall, understanding these interdependent parameters can improve the current mAb-based formulations and develop novel mAb-based therapeutics for achieving durable clinical outcomes in a large subset of patients.

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Pancreatic cancer (PC) is a highly lethal malignancy with a 5-year survival rate of 10%. The occurrence of metastasis, among other hallmarks, is the main contributor to its poor prognosis. Consequently, the elucidation of metastatic genes involved in the aggressive nature of the disease and its poor prognosis will result in the development of new treatment modalities for improved management of PC. There is a deep interest in understanding underlying disease pathology, identifying key prognostic genes, and genes associated with metastasis. Computational approaches, which have become increasingly relevant over the last decade, are commonly used to explore such interests. This review aims to address global studies that have employed global approaches to identify prognostic and metastatic genes, while highlighting their methods and limitations. A panel of 48 prognostic genes were identified across these studies, but only five, including ANLN, ARNTL2, PLAU, TOP2A, and VCAN, were validated in multiple studies and associated with metastasis. Their association with metastasis has been further explored here, and the implications of these genes in the metastatic cascade have been interpreted.