Marc Laurence Mendillo - HSF1 and Molecular Chaperones in Biology and Cancer

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Proteostasis, or protein homeostasis, is a fundamental requirement for fitness in cells across all kingdoms of life. The proteostasis network encompasses pathways that synthesize, fold, and degrade cellular proteins. Deregulation of these pathways has devastating consequences to organismal health, leading to a range of pathological conditions including developmental defects, neurodegenerative diseases, and cancer. The compendium of chapters in this book focuses on the structure, function, and therapeutic implications of the proteostasis machinery in cancer.

We have been fortunate to receive contributions from an extraordinary group of basic, clinician, and translational scientists with a range of research approaches and expertise that include biochemistry, molecular biology, genetics, structural biology, and chemical biology. Underscoring the deep conservation and critical importance of this field of study, these researchers employ model systems from yeast to human to interrogate the underlying mechanisms and functional significance of the proteostasis network in health and disease. While a diverse group, these scientists are unified by a passion and belief that understanding the mechanistic basis by which proteins the molecular machines of the cell are able to fold and function properly is critical to understanding nearly all aspects of tumorigenesis. The chapters in this book reflect this fundamental tenet and cover the structural and biochemical properties of the major chaperone systems in the cell, how these chaperone systems function to impact cancer cells and the tumor microenvironment, and the promise of targeting these systems as an anticancer therapeutic strategy.

We chose to take this initiative to celebrate and commemorate the work of our beloved late mentor, Susan Lee Lindquist, a pioneer of proteostasis. Susan started her work on heat-shock proteins in the 1970s as a PhD student in the lab of Matthew Meselson at Harvard University. After completion of her PhD in 1976 and a brief postdoctoral fellowship at the University of Chicago, she joined the faculty at the University of Chicago where she embarked her independent research on protein synthesis and folding before moving to the Whitehead Institute for Biomedical Research at MIT. Switching to new model organisms as the biological questions required, Susan electrified the field time and time again using cutting-edge methods and incisive experiments to reveal new concepts that laid the foundation of what would later become known as proteostasis.

Her work on heat-shock proteins, prions, and amyloids in model organisms led her to realize that the interface between protein homeostasis and environmental stress might be involved in the evolution of new traits. This insight crystalized into the paradigm-shifting concept of Hsp90 as a capacitor of evolution. A decade later, she showed that similar protein-based evolutionary mechanisms fuel the malignant progression and therapeutic resistance of cancers.

Sadly, Susan succumbed to the disease she had been studying. On 27 October 2016, she died of ovarian cancer at the age of 67. The scientific community lost a hero that day. A scientific pioneer, role model, and advocate for women in STEM, Susans impact lies not only in her discoveries but also in her contributions to the culture of science. Her mentorship, the collegial environment she fostered, her curiosity, and her scientific enthusiasm made her into the iconic scientist she was and whom we dearly miss.

This book is dedicated to you, Sue.