Saif project receives CCIL 2021 seed award
MechSE professor Taher Saif leads one of nine Illinois interdisciplinary research teams selected for the Cancer Center at Illinois (CCIL) annual seed grant awards.
Since launching in 2019, CCIL seed grant funding has supported interdisciplinary cancer research projects that facilitate cross-campus collaboration. Previous grant projects have led to a number of additional external funding opportunities, including a recent $1.25M NIH grant to further explore breast cancer progression.
“Due to the proven success of the CCIL Seed Grant Program, we were able to support additional initiatives in 2021 compared to previous years,” Paul Hergenrother, CCIL Deputy Director, said. “CCIL scientists are making bold discoveries and leading innovative initiatives that will create technologies and techniques that will translate from labs to clinics. The depth of science, engineering, and technology expertise at the University of Illinois Urbana Champaign will transform the cancer industry for years to come.”
Saif’s project is titled “FORce Control of Cancer Tumor μEnvironment (FORCE).” His research team consists of Kimberly Selting, Department of Veterinary Clinical Medicine; Kannanganattu V. Prasanth, Department of Cell and Developmental Biology; and Hyunjoon Kong, Department of Chemical & Biomolecular Engineering.
Tumor growth and metastatic transition of cancer cells are determined by a dynamic crosstalk between the malignant cells and the tumor microenvironment. The latter consists of stromal cells, mostly dominated by cancer associated fibroblasts (CAF), together with various other cells, and extracellular matrix (ECM). CAFs generate mechanical contractile force. They remodel the matrix by mechanically pulling and aligning the ECM fibers, and by releasing ECM contents and crosslinkers. Remodeled matrix favors migration of invasive cancer cells. CAFs also support cancer cells by releasing metastasis promoting factors, such as chemokines, and by receiving factors from them. In spite of known contractility, the mechanistic role of CAF force on cancer progression remains elusive. While the current literature views the many participants of tumor microenvironment as interacting emergent entities, it does not identify any potential universal driver that mediates this emergence. And yet, if such a driver can be identified and characterized, then its function can be interrupted to disrupt the circuit of cancer progression. We argue, based on our preliminary evidence, that CAF force can be such a driver. CAFs assume diverse functions by adjusting their force. CAFs also change force with external stimulations, such as radiation. We thus propose the FORCE hypothesis: (I) CAFs promote metastatic progression through force-dependent (a) release of growth factors for cancer cells, and (b) ECM remodeling; and (II) radiation increases CAF force. We will test the hypothesis using human colon tumor cell lines (CAF05, cancer cells: FET, low (SW480), high metastatic (SW620)), and a high-resolution micro force sensor recently developed by the PI. The specific aims are: (Aim 1) Test whether CAF force influences gene expressions, growth factor release, and cross talk with cancer cells, and whether force is modified by radiation. CAF05 will be plated on polyacrylamide (PA) 2D gel substrate with appropriate stiffness so that CAF force is 150, 600 and 4000 nN per cell. A 2D substrate with cancer cells will be brought close to the CAF substrate, both sharing the common media facilitating their cross talk through released factors. The effect of increasing CAF force will be assessed by quantifying (a) transformation of cancer cells from low to higher invasive state, and their gene expression using RNA-seq (b) expression of cancer promoting factors by CAFs, and corresponding receptors by the cancer cells, all with and without radiation of CAF05 and CAF05-cancer cell system. (Aim 2) Test whether CAF force remodels ECM, favoring cancer cell migration. A 3D micro tissue, formed by CAF05, FET cells and collagen-1, will be integrated with the force sensor. The effect of cell force, with and without radiation, will be assessed by monitoring tissue remodeling (stiffness by the sensor, ECM architecture by Second Harmonic Generation imaging), metastatic phenotype of cancer cells (migration), expressions of cancer promoting genes by CAF05 (RNA-FISH seq), all as a function of CAF force history. In order to assess the potential of cancer management by decreasing CAF force, tests on microtissues will be repeated with mutated CAF05 with reduced contractility.