Investigating the metabolic regulation of tumor desmoplasia

Abstract public domain (NIH RePORTER)

PROJECT SUMMARY/ABSTRACT The ability of fibroblasts to synthesize extracellular matrix (ECM) proteins is critical for wound healing; however, this program is coopted by cancer cells in multiple solid tumors, resulting in the formation of cancer-associated fibroblasts (CAFs) that drive a desmoplastic response which contributes to cancer progression and promotes therapy resistance. Collagen is the most abundant protein in the ECM and has a unique amino acid composition such that up to 25% of its sequence is represented by proline. Proline is a limiting metabolite for collagen synthesis in CAFs, and CAFs promote proline biosynthesis by increasing mitochondrial glutaminolysis and directing the resulting glutamate into the proline biosynthetic pathway instead of its utilization as an anaplerotic substrate for the TCA cycle. However, the mechanism directing the differential utilization of glutamine for proline or the TCA cycle is not understood. Besides, glutamine is depleted in many solid tumors such as pancreatic ductal adenocarcinoma (PDAC), but paradoxically, collagen is highly abundant in PDAC. The objective of the present proposal is to gain a better understanding of the unique metabolic requirements for collagen production in CAFs and thereby identify novel targets to reduce tumor desmoplasia. The proposed studies are aimed at determining how CAFs redirect glutamine into proline biosynthesis (Aim 1) and identifying the adaptive mechanisms by which CAFs sustain collagen production when extracellular glutamine is limited (Aim 2). Finally, I will investigate whether targeting these adaptive mechanisms is a strategy to reduce desmoplasia in PDAC without affecting matrix production in healthy tissues (Aim 3). The scientific knowledge gained from these studies as well as my research training plan will help me to develop a unique research program and facilitate transition into to independence, with the long-term goal to study the mechanistic basis of tumor-stroma crosstalk and to apply this knowledge to develop therapeutic strategies that can improve outcomes of cancer patients. In addition to my research objectives, I have outlined a detailed career development plan that will help me obtain important skills for leading an independent research laboratory, including teaching and mentoring skills, scientific communications, grant writing and laboratory management. I will work towards my goals under the mentorship of Dr. Craig Thompson, a leader in cancer metabolism with a stellar track record of trainees that went on to faculty positions. In addition, I have assembled an Advisory Committee that will collaborate and meet with me regularly to help me perform the proposed experiments and develop into an independent researcher. This team includes Dr. Justin Cross with expertise in metabolomics, Dr. Scott Lowe with expertise in mouse models of cancer, Dr. Joshua Rabinowitz with expertise in studying metabolic flux in vivo, and Dr. Gina Sizemore with expertise in studying tumor-stroma interactions. My research and career development plan, together with my mentor, advisors and the exceptional academic environment at Memorial Sloan Kettering Cancer Center will provide a solid ground on which I can build a career as an independent investigator in cancer metabolism.

Public health relevance public domain (NIH RePORTER)

PROJECT NARRATIVE Many solid tumors display a desmoplastic response characterized by an extensive deposition of collagen by cancer-associated fibroblasts (CAFs) which contributes to cancer progression and promotes therapy resistance. The proposed research will investigate the metabolic regulation of collagen production in CAFs. A better understanding of the unique metabolic requirements for CAF-mediated collagen production will help to identify targets to reduce tumor desmoplasia and thereby create novel therapeutic vulnerabilities.