Decoding the obesity-cancer connection: lessons from preclinical models of pancreatic adenocarcinoma

Abstract

Obesity is a metabolic state of energy excess and a risk factor for over a dozen cancer types. Because of the rising worldwide prevalence of obesity, decoding the mechanisms by which obesity promotes tumor initiation and early progression is a societal imperative and could broadly impact human health. Here, we review results from preclinical models that link obesity to cancer, using pancreatic adenocarcinoma as a paradigmatic example. We discuss how obesity drives cancer development by reprogramming the pretumor or tumor cell and its micro- and macro-environments. Specifically, we describe evidence for (1) altered cellular metabolism, (2) hormone dysregulation, (3) inflammation, and (4) microbial dysbiosis in obesity-driven pancreatic tumorigenesis, denoting variables that confound interpretation of these studies, and highlight remaining gaps in knowledge. Recent advances in preclinical modeling and emerging unbiased analytic approaches will aid in further unraveling the complex link between obesity and cancer, informing novel strategies for prevention, interception, and therapy in pancreatic adenocarcinoma and other obesity-associated cancers.

Figure 1.. Causes and consequences of obesity.

Graphical illustration of host and exogenous factors contributing to obesity and the resultant physiologic effects that promote cancer development.

Figure 2.. Worldwide trends in obesity rates and fat consumption.

(A) The proportions of obese (body mass index>30) or obese + overweight (body mass index>25) individuals have increased rapidly worldwide and at a much more alarming rate in Western countries (e.g., United States (US)) over the last 50 yr. Data sourced from the World Health Organization. (B) Per-capita fat consumption (grams per day) by source (animal versus vegetable) over the last 60 yr. Data sourced from the Food Agricultural Organization of the World Health Organization.

Figure 3.. Obesity-associated metabolic alterations in advanced PDAC tumors.

PDAC tumors grown in HFD-fed mice exhibit increased tumor growth and dependency on nitrogen flux through arginase (ARG2) and stress granule formation via a signaling axis encompassing insulin-like growth factor 1 (IGF1), phosphoinositide 3-kinase (PI3K), mammalian target of rapamycin (mTOR), S6 kinase (S6K1), and serine–arginine protein kinase 2 (SRPK2). Nodes for inhibition that suppress tumor growth in vivo are noted in red.

Figure 4.. Obesity-associated hormone dysregulation as a driver of tumorigenesis.

Aberrant expression of endocrine hormones promotes tumorigenesis at various stages of development. β cell hormones (insulin and CCK) act directly on acinar cell receptors (InsR and CCKAR, respectively) to promote acinar-to-ductal metaplasia (ADM), a prerequisite step in early PDAC development. Lcn2 from adipocytes and/or neutrophils (polymorphonuclear cells) induces tumor growth and cachexia via distinct receptors (Slc22a17 and MC4R, respectively). Potential nodes for inhibition that suppress early tumor development or advanced tumor growth in vivo are noted in red.

Figure 5.. Obesity-induced inflammation as a driver of tumor initiation and growth of PDAC.

(A) PanIN formation in obese mice is associated with increased myeloid infiltratration (denoted by pink neutrophils and blue macrophages) and fibrosis (denoted by purple stellate cell and collagen fibers). This can be blocked by targeting inflammatory pathways including COX2 and TNFα/TNFR1 signaling. Aspirin induces expulsion of Ras-transformed pancreatic duct cells (red). (B) Reciprocal IL1β-mediated interactions between adipocytes, tumor-associated neutrophils (TANs), and pancreatic stellate cells (purple) induce fibrosis, reduce perfusion impairing chemotherapeutic response, promote NETosis (formation of neutrophil extracellular traps), suppress cytotoxic CD8⁺ T cell infiltration, and in turn, promote tumor growth. Potential nodes for inhibition that suppress tumor growth in vivo are noted in red.