Abstract 65: Gel-forming mucin MUC5AC as the nexus for cell-adhesion molecules governing pancreatic cancer aggressiveness and chemoresistance

Abstract

Abstract Background: Pancreatic cancer (PC) ranks as the third leading cause of cancer-related deaths in the U.S. Poor prognosis of this malignancy stems from propensity for early metastasis and resistance to chemotherapeutic drugs. Tumor-associated extracellular matrix (ECM) plays a key role in impeding drug penetration and regulating tumor aggressiveness by modulating the cell-adhesion molecules and cytoskeletal rearrangement. Heavily glycosylated secreted mucin MUC5AC, one of the most differentially expressed molecule in PC, is associated with poor prognosis of PC patients. We hypothesize, MUC5AC, with the virtue of its gel forming property, promotes tumor-associated ECM deposition that impedes intratumoral drug delivery. Further, abrogation of MUC5AC decreases PC cell aggressiveness and chemoresistance by acting as an interacting nexus for multiple cell-surface mechanotransducers. Results: RNA sequencing and immunohistochemical analysis revealed significant decrease in profibrotic factors like fibronectin, collagen and α-smooth muscle actin in the pancreatic sections of KCM (KrasG12D; Pdx1-Cre; Muc5ac-/-) mice as compared to KC (KrasG12D; Pdx1-Cre) mice along PC progression. Second harmonic generation imaging revealed less cross-linked collagen organization in KCM as compared to KC. Further, decrease in invasive precursor lesions (p<0.01) and Ki67-positive proliferative cells were observed in KCM mice pancreas. Orthotopic transplantation of human PC cells showed decreased tumor weight (p<0.05) and metastatic incidences upon MUC5AC knock-down (KD). A global mechanistic insight using gene set enrichment analysis from RNA seq. data suggested significant downregulation in genes involved in cell-adhesion, cell-migration and ECM organization in the KCM mice. Among the cell-adhesion molecules, MUC5AC was found to interact with E-cadherin and CD44 on the surface of human PC cells and mouse-derived organoids. Furthermore, MUC5AC expressing cells showed high expression of integrin αvβ5 and pSrc/ pSTAT3 activation. Additionally, MUC5AC-KD cells and organoids from KCM mouse pancreas exhibited greater apoptotic propensity with lesser nuclear localization of β-catenin upon gemcitabine treatment as compared to control. Pharmacologic inhibition of β-catenin nuclear localization sensitized the MUC5AC expressing cells and organoids to gemcitabine. Conclusion: Our results indicate that gel-forming mucin MUC5AC serves as key node for cell-cell and cell-matrix interactions thereby leading to bidirectional pro-tumorigenic signaling in PC. While, MUC5AC may disrupt E-cadherin-based intercellular junctions to promote transcriptional activation of β-catenin and thereby chemoresistance in PC cells; it also aggravates PC progression and desmoplasia via integrin-mediated mechanosensing. Citation Format: Koelina Ganguly, Shiv Ram Krishn, Rahat Jahan, Pranita Atri, Satyanarayana Rachagani, Sanchita Rauth, Huang Xi, Yongfeng Lu, Surinder Batra, Sukhwinder Kaur. Gel-forming mucin MUC5AC as the nexus for cell-adhesion molecules governing pancreatic cancer aggressiveness and chemoresistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 65.