Investigating the bidirectional tumor-host crosstalk in cachexia and pancreatic ductal adenocarcinoma

Abstract public domain (NIH RePORTER)

PROJECT SUMMARY/ABSTRACT Pancreatic ductal adenocarcinoma (PDAC) is the prototypical cancer associated with cachexia, a paraneoplastic syndrome that manifests as wasting of adipose tissue depots and muscle atrophy that reduces overall survival. PDAC patients exhibit the highest rates and most severe forms of cachexia across all cancer types, with ~80% of PDAC patients presenting with cachexia, and ~30% of patients succumbing to cachexia-associated complications. Currently, there are no therapeutic interventions to reverse or block cachexia, underscoring the need for meticulously investigating the novel molecular drivers of cachexia onset. Emerging clinical data shows that PDAC patients exhibit signs of cachexia up to ~18 months before PDAC diagnosis, at a stage when patients often present with chronic pancreatitis (CP). CP patients have an elevated risk of PDAC and experience significant weight loss prior to a cancer diagnosis. We will thus study cachexia onset in CP models to understand the molecular etiology of cachectic wasting. In addition to pancreatitis, obesity is associated with higher PDAC incidence, and obese PDAC patients have dysregulated adipose signaling that putatively alters cancer associated adipocyte-tumor cell crosstalk. Thus, the focus of this Early K99/R00 application is to investigate early stages of benign pancreatic disorders, such as CP and obesity in cachexia and PDAC, respectively. Our recent work shows that tumor-derived PTHrP is a master regulator of cachexia in PDAC, and PTHrP is upregulated during CP, but a causal role for PTHrP in initiating cachexia during pancreatitis has not yet been explored. In AIM 1 (K99 phase), we will characterize the functional role of PTHrP in causing pancreatitis- associated cachexia using PTHrP-centric mouse models we have developed. In AIM 2 (K99 phase), we will investigate novel mediators of cachexia during CP at the metabolic, transcriptomic, and proteomic levels to establish an integrated framework that informs their functional role in driving cachectic wasting. At the completion of these aims, we will have built a multi-organ timeline of CP-associated wasting that can signal an upcoming PDAC diagnosis and inform therapy regimens. In AIM 3 (R00 phase), we will interrogate how obesity and impaired adipose signaling networks promote PDAC initiation and progression. The bidirectional crosstalk between the host and tumor during premalignant and malignant transformation will greatly accelerate our understanding of this deadly malignancy and aid in designing robust therapeutic strategies. The K99 aims will be accomplished by training with Dr. Jason Pitarresi, an expert on pancreas cancer and cachexia mouse modeling, and under the co-mentorship of metabolism expert, Dr. David Guertin. I will obtain additional technical and career development from my K99/R00 advisory committee, consisting of Dr. Cholsoon Jang, Dr. Evan Rosen, Dr. Julie Xue, Dr. Anirban Maitra, and Dr. Jessica Spinelli. The successful completion of this study will lead to a panel of novel functional mediators of cachexia during early premalignant stages and elucidate the role of dysregulated adipose in PDAC development.

Public health relevance public domain (NIH RePORTER)

PROJECT NARRATIVE Pancreas cancer is one of the deadliest malignancies with co-morbidities from cachexia and obesity contributing substantially to poor patient survival outcomes. The molecular landscape of cachexia in pancreatitis and obese patients, who are at the highest risk of developing pancreas cancer, is largely unknown, leading to a lack of efficient therapeutic strategies and dismal relative 5-year survival rates. In the K99 phase, we will investigate the mechanistic processes for cachexia onset during chronic pancreatitis prior to pancreatic cancer and, during the R00 phase we will interrogate the effect of obesity and dysregulated adipose signaling in pancreas cancer development to inform future translational studies.