ECM geometrical and mechanical properties modulate RTK signaling
List of Collaborating Institutions
University of California, Berkeley
University of California, San Francisco
A serious problem with cancer treatment today is the tendency of cancer cells to develop resistance to the drugs we use to destroy them. The devastating result is that all too many cancer patients see their cancer at first respond positively to drug treatment, only to return later with a newfound resistance to the cancer drugs. A combination of discoveries from the Groves lab (physical chemistry, UCB) and the Weaver lab (cancer biology, UCSF) have lead to a new insight into how cancer cells acquire this resistance and how we might be able to stop this deadly process.
Receptor tyrosine kinase (RTK) somatic mutations and overexpression are found in many aggressive diseases such as non-small cell lung carcinoma (NSCLC), breast cancer, and colorectal cancer. RTKs are thus important targets for cancer therapy. However, patients often develop resistance to RTK inhibitors, despite initially robust tumor regression. While this could be due to the emergence of mutated clones, stromal-epithelial interactions also regulate tumor progression and treatment response. In particular, there is a striking heterogeneity in extracellular matrix (ECM) mechanical properties in diseased tissue. Recent work from our groups suggests that ECM modulation of tumor behavior occurs through RTK signaling assemblies (Weaver et al., Cell, 2009; Nature, 2014; Cancer Res., 2014; Groves et al., Science, 2010), extending the mechanistic features of the mechano-signal initiation beyond the well-characterized effect of integrin-mediated adhesion and signaling. It is our thesis that in addition to genetic variation, external spatio-mechanical factors from the ECM are critical contributors to RTK therapy resistance. In this program, we will utilize the expertise of both of our groups to quantitatively characterize and manipulate the mechanical and topographical properties of the cellular microenvironment to understand the effects on RTK signaling (Figure), and its therapeutic inhibition. This study will provide actionable insights by pinpointing the molecular mechanisms by which ECM modulates RTK signaling and contributes to RTK inhibitor resistance.
Figure: Schematic of proposed research to study how the mechanical and topographical properties of the cellular microenvironment modulate RTK signaling and contribute to RTK inhibitor resistance in cancer treatment.
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Jay Groves, Ph.D.
The Groves lab focuses on chemistry in complex environments where, for example, collective properties of the system feedback onto the molecular scale chemical events. Such multi-scale coupling is widespread in biological systems, from dynamical movements within a protein to morphological transitions of whole cells. The lab pursues a variety of research projects emphasizing physical mechanisms of molecular self-organization and the role of spatial patterning as a regulator of differential outcomes from otherwise chemically equivalent systems.
Valerie M. Weaver, Ph.D.
Valerie M. Weaver, Ph.D., is the Director of the Center for Bioengineering and Tissue Regeneration in the Department of Surgery and Associate Professor in the Department of Surgery and Anatomy and Bioengineering and Therapeutic Sciences at UCSF. Her group studies the molecular mechanisms whereby extracellular matrix receptors and mechanical force and matrix topology modulate normal and transformed cell behavior and alter embryonic cell fate. The research involves bioengineered matrices, microscopy techniques (traction force microscopy, atomic force microscopy, second harmonic generation microscopy), cell biology and animal work.
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