Indian Scientists, Jamia alumnus discover the role of CCN1 gene in Pancreatic Cancer Development

By Staff Reporter,

Kansas City: The findings of a study on a special protein in pancreatic cancer progression, known to be an angiogenic factor called CCN, co-authored by an alumnus of Jamia Millia Islmia have been published in prestigious The Scientific Reports (Nature publishing group) in May 2014.

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Pancreatic cancer is an exceptionally aggressive disease, which is not easily detectable and the five year survival rate for patients is less than 5%. It represents the fourth leading cause of cancer-related deaths in the United States. Although pancreatic cancer is less common in India compared to western countries but now incidences of pancreatic cancer are increasing day by day. The disease affects one in 100,000 Indians.

Dr. Inamul Haque
Dr. Inamul Haque

A former student of the Department of Biosciences of the New Delhi’s Jamia Millia Islamia (from 1991 to 2005), Dr. Inamul Haque, a co-author and an assistant professor at the University of Kansas Medical Center told through email that the aim of the study was to uncover the role of CCN1 during the communication of pancreatic cancer cells and endothelial cells in induction of tumor angiogenesis/aberrant neovascularization.

CCN1, is a matricellular protein of CCN-family, plays a vital role in pancreatic cancer progression and metastasis. Dr. Haque’s earlier findings published in the Journal of Biological Chemistry in 2013 concluded that CCN1 impacts both sonic hedgehog (SHh) and Notch pathways through integrins in pancreatic cancer cells. Both SHh and Notch signalling influence pancreatic tumor growth and contribute in the formation of tumor angiogenesis (blood vessel formation) in pancreatic cancer and other solid cancers.

“During embryonic development, CCN1 acts as an angiogenic factor, and pro-angiogenic activities of CCN1 are mediated through integrins in human umbilical vein endothelial cells which form the inner lining of blood vessels. In pancreatic cancer, the tumor cells secrete CCN1 which contributes in angiogenesis,” said Dr. Haque.

“Tumor blood vessels are different than regular blood vessels. Tumor vessels are sluggish and leaky, so when we try and treat cancer with drugs they can’t easily reach the tumor because the vessels aren’t strong,” said Drs. Sushanta Banerjee and Snigdha Banerjee, professors from the University of Kansas Medical Center and principal investigators of the study.

However, the role of CCN1 in aberrant blood vessel formation in pancreatic cancer remains unclear.

The lead author of the study, Dr. Gargi Maity, a post-doctoral fellow said: “Our combined data from different in vitro and in vivo experimental approaches displayed that pancreatic cancer cell-secreted-CCN1 promotes endothelial cell migration and aberrant capillary formation. We find that tumor angiogenic response of CCN1 was strongly dependent upon the tumor microenvironment.”

Understanding this process can lead to better targeted therapies for pancreatic cancer. When the researchers knocked down the CCN1 protein using shRNA, very few vessels and capillaries formed under mouse skin. This finding suggests that finding or creating a drug that silences CCN1 could slow down or even stop pancreatic cancer tumors from growing. “The next step would be to find an existing drug that can target the CCN1 protein, or create one,” said Dr. Snigdha.

“Our studies demonstrate that CCN1 of pancreatic cancer cells is vital for the regulation of tumor angiogenesis and thus could be an ideal target for tumor vascular disruption in pancreatic cancer,” the Banerjees concluded.

Journey from Jamia to USA:

Dr. Inamul Haque was a bonafide student of a central university of Jamia Millia Islamia for about 14 years (from Bachelor, Masters, B.Ed to PhD). He did his PhD under the supervision of Professor Faizan Ahmad, a well-known protein biochemist.

During PhD program, he had investigated the effect of a class of compatible osmolyte (polyols) on the thermodynamic mechanism of stabilization of proteins by these chemical chaperones. Results from his doctoral work have been published in five peer reviewed journals (J. Biol. Chem. 2005, 138, 11035-11042; Biophysical Chemistry 2005, 117, 1-12; FEBS Letters. 2005, 579, 3891–3898; Biophysical Chemistry 2006, 119, 224-233; Biochim. Biophys. Acta 2007, 1774, 1555-1562).

In 2006, Dr. Haque moved to USA in the laboratory of Dr. Mark Fisher, University of Kansas Medical Center, Kansas City, Kansas as a postdoctoral fellow. He worked with Dr. Fisher for a year on GroEL-assisted protein folding in presence of different osmolytes (Biopolymers 93:237-252).

In Fisher lab, Dr. Haque learnt many state of the art techniques including electron cryo-microscopy. Seven years ago, Dr. Sushanta Banerjee offered him a postdoctoral position. Dr. Haque was delighted to accept his offer and he realized that his dream to be cancer biologist is going to be true. In fact, he had a strong interest and commitment in the field of cancer research since he was in my doctoral program.

Left to right: Dr. Gargi Maity, Dr. Inamul Haque, Dr. Snigdha Banerjee and Dr. Sushanta Banerjee.
Left to right: Dr. Gargi Maity, Dr. Inamul Haque, Dr. Snigdha Banerjee and Dr. Sushanta Banerjee.

In Dr. Banerjee’s laboratory at Veterans Affairs Medical Center, Kansas City, MO, he was involved in the drug and alternative medicine testing in animal xenograft models. He studied the regulation of microRNA by CCN5/WISP-2, a member of CCN (cysteine-rich 61-connective tissue growth factornephroblastoma-overexpressed) family of growth factors. Dr. Haque found that nullification of CCN5/WISP-2 in ER-positive noninvasive breast tumor cell upregulates the miR-10b expression (Banerjee et al., Cancer Research 2008, 68:7606-12; Haque 2011, J. Biol. Chem. 286(50):43475-85). Based on these unique findings, he proposed a model in which CCN5 signaling has a central role in non-invasive to invasive transition followed by metastasis.

In another parallel study (Haque et al., 2011 Molecular cancer 10:8), he reported that Cyr61/CCN1, another member of CCN family plays a critical role in pancreatic carcinogenesis through the induction of EMT and stemness. In a recent study, he noticed that Cyr61/CCN1 is a crucial regulator of Sonic Hedgehog in pancreatic cancer (Haque et al., J. Biol. Chem. 2012, 287 (46): 38569–38579). These studies were highlighted last years in reputed Indian newspapers like the Times of India, the Hindustan, urdu daily Inquilab and others.

Recently, he worked in the collaboration with Dr. Suman Kambhampati, associate professor of Medicine in Hematology/Oncology, University of Kansas Medical Center, Kansas City on the efficacy of 2-methoxyestradiol (2-ME2), a novel antitumor and antiangiogenic agent on Barrett’s esophageal adenocarcinoma. They indicate that its prodrug could be a potential candidate in novel treatment strategies for Barrett’s esophageal adenocarcinoma (Kambhampati et al., Mol. Cancer Ther. 2010, 9:523-34; Kambhampati et al., Mol. Cancer Ther. 2012, 12(3):255-63). This work was highlighted by this journal and one of this article’s figures was selected for cover page of this issue. Recently, his novel study found that CCN5 upregulates and stabilizes p27 through AKT/FOXO3a signalling in breast adenocarcinoma (Haque et al., Oncogene 2014, revision submitted).

Moreover, extended work of his pancreatic project reports that CCN1 signaling activates Sonic Hedgehog through autocrine-paracrine circuits to promote endothelial cell migration and tumor angiogenesis and suggest that CCN1 signaling of pancreatic cancer cells is vital for the regulation of tumor angiogenesis (Maity et al., Scientific Reports 2014, 4 : 4995 | DOI: 10.1038/srep04995 ). Currently, Dr. Haque is an assistant professor in the department of Hematology/Oncology, Internal Medicine ( and actively collaborating with different investigators in the Cancer Research Unit at VA Medical Center, Kansas City, including Dr. Sushanta Banerjee, Dr. Snigdha Banerjee, Dr. Suman Kambhampati and others. His personal interest is kidney cancer as this is a very poorly developed field in cancer biology.

Dr. Haque aims to decipher the effect of Englerina, a molecule of herb (Phyllanthus engleri) extract alone and in combination with FDA approved drugs on tumor cell growth and proliferation in vitro and in vivo to enhance the efficacy of these drugs.