Cancer

Cancer

Overview

According to the World Health Organization (https://www.who.int/), cancer is the second leading cause of death globally, accounting for nearly 10 million deaths in 2020 alone. Cancer cells begin as normal cells that go through a multi-stage process to become cancerous and then eventually become a tumor. However, tumors are not made up of only cancer cells. They also contain normal cell types and extracellular molecules that surround, support, and feed the cancer cells. There is abundant communication between cancer cells and the normal elements in the body’s environment. This means that the tumor can change its environment and the environment can affect how a tumor will grow and spread.

San Diego BioMed scientists are contributing to the fight against cancer by focusing on limiting the invasion of cancer cells and learning how to target the microenvironment surrounding the tumor to keep the cancer from spreading.

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Studies

The ElShamy group

Dr. ElShamy’s research interests encompass basic, clinical, and translational research. The research projects in his lab focus on identifying and improving treatments for breast and ovarian cancer, especially metastatic diseases in which tumors will develop and spread to other areas of the body. The ongoing research conducted by the ElShamy group is based on the hypothesis that tumor cell dissemination and metastasis is an early event and not an end point of the disease. If this hypothesis is correct, this means that current treatment options will fail to target the true killer, the metastatic precursors that have already spread.

The ElShamy lab is specifically focused on tackling breast cancer as an interactive entity composed of tumor cells and their microenvironment. The tumor microenvironment contains a variety of activated entities such as adult stem cells (mesenchymal stem cells) and white blood cells (macrophages and other immune cells) which are intimately involved in promoting tumor progression and spreading cancer to other organs. The ElShamy approach aims to therapeutically target both the microenvironment and the tumor cells to achieve a higher level of remission. The hope is that, if successful, this information will allow us to develop novel therapeutic regimens to block tumor progression and therapeutic resistance.

The DerMardirossian group
A major challenge in cancer is identifying ways to limit the invasion of cancer cells. One approach to prevent invasion is to find ways to block the way cancer cells respond to environmental signals that encourage them to migrate. Cells move decisively in a particular direction by creating temporary structures called lamellipodia and filopodia, that emerge like fingers to initiate and direct cell migration. The DerMardirossian group focuses on dissecting the underlying biological factors and pathways that regulate lamellipodia and filopodia development and movement. This information is critical to our understanding of the mechanisms underlying normal physiological function of cells and the consequence of deregulation in pathological conditions such as cancer.

A critical factor in the process that results in cell movement is the ability of cells to coordinate signaling pathways with the movement of physical structures in the cells, otherwise called, cytoskeleton dynamics. Many tumors increase their expression and/or activation of proteins known as RhoGTPases, GEFs, and GAPs. These are critical coordinators of the cytoskeleton machinery, making them key players for cells movement.
Ongoing projects in the DerMardirossian lab include the analysis of the role of RhoGTPases, GEFs, and GAPs, and a series of new binding partners that have been recently discovered by the DerMardirossian group, in regulating lamellipodia, filopodia, and subsequently cell migration and cancer invasion. This information will be used to design new strategies to control the aberrant activation of RhoGTPases, their regulators, and cancer metastases.

Experimental approaches used in the DerMardirossian lab include biochemistry, state-of-the-art confocal microscopy, high-throughput screening, computational methods for drug design, and pre-clinical cancer migration models.

Select Publications

Blanchard Z, Paul BT, Craft B, ElShamy WM. BRCA1-IRIS inactivation overcomes paclitaxel resistance in triple negative breast cancers. Breast Cancer Res. 2015 Jan 13;17:5.

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Sinha A, Paul BT, Sullivan LM, Sims H, El Bastawisy A, Yousef HF, Zekri AN, Bahnassy AA, ElShamy WM. BRCA1-IRIS overexpression promotes and maintains the tumor initiating phenotype: implications for triple negative breast cancer early lesions. Oncotarget. 2017 Feb 7;8(6):10114-10135.

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Gardner L, Malik R, Shimizu Y, Mullins N, ElShamy WM. Geminin overexpression prevents the completion of topoisomerase IIα chromosome decatenation, leading to aneuploidy in human mammary epithelial cells. Breast Cancer Res. 2011 May 19;13(3):R53.

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Blanchard Z, Mullins N, Ellipeddi P, Lage JM, McKinney S, El-Etriby R, Zhang X, Isokpehi R, Hernandez B, Elshamy WM. Geminin overexpression promotes imatinib sensitive breast cancer: a novel treatment approach for aggressive breast cancers, including a subset of triple negative. PLoS One. 2014 Apr 30;9(4):e95663.

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Ananthula S, Sinha A, El Gassim M, Batth S, Marshall GD Jr, Gardner LH, Shimizu Y, ElShamy WM. Geminin overexpression-dependent recruitment and crosstalk with mesenchymal stem cells enhance aggressiveness in triple negative breast cancers. Oncotarget. 2016 Apr 12;7(15):20869-89.

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Ryan D, Sinha A, Bogan D, Davies J, Koziol J, ElShamy W. A niche that triggers aggressiveness within BRCA1-IRIS overexpressing triple negative tumors is supported by reciprocal interactions with the microenvironment. Oncotarget. 2017 8:103182-103206.

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Dagliyan O, Karginov AV, Yagishita S, Gale ME, Wang H, DerMardirossian C, Wells CM, Dokholyan NV, Kasai H, Hahn KM. Engineering Pak1 Allosteric Switches. ACS Synth Biol. 2017 Jul 21;6(7):1257-1262. doi: 10.1021/acssynbio.6b00359. Epub 2017 Apr 6. PMID: 28365983; PMCID: PMC5562282.

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Our research programs are funded primarily by grants from the National Institutes of Health (NIH). Private donations help to accelerate the progress of research through the purchase of laboratory supplies and equipment or the recruitment of additional laboratory personnel. Thank you!

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