Morphological Heterogeneity in Pancreatic Cancer Reflects Structural and Functional Divergence

Abstract

Inter- and intratumor heterogeneity is an important cause of treatment failure. In human pancreatic cancer (PC), heterogeneity has been investigated almost exclusively at the genomic and transcriptional level. Morphological heterogeneity, though prominent and potentially easily assessable in clinical practice, remains unexplored. This proof-of-concept study aims at demonstrating that morphological heterogeneity reflects structural and functional divergence. From the wide morphological spectrum of conventional PC, four common and distinctive patterns were investigated in 233 foci from 39 surgical specimens. Twenty-six features involved in key biological processes in PC were analyzed (immuno-)histochemically and morphometrically: cancer cell proliferation (Ki67) and migration (collagen fiber alignment, MMP14), cancer stem cells (CD44, CD133, ALDH1), amount, composition and spatial arrangement of extracellular matrix (epithelial proximity, total collagen, collagen I and III, fibronectin, hyaluronan), cancer-associated fibroblasts (density, αSMA), and cancer-stroma interactions (integrins α2, α5, α1; caveolin-1). All features differed significantly between at least two of the patterns. Stromal and cancer-cell-related features co-varied with morphology and allowed prediction of the morphological pattern. In conclusion, morphological heterogeneity in the cancer-cell and stromal compartments of PC correlates with structural and functional diversity. As such, histopathology has the potential to inform on the operationality of key biological processes in individual tumors.

Collagen Organization Does Not Influence T-Cell Distribution in Stroma of Human Pancreatic Cancer

“…Generally, fibrillar collagen is highly abundant in the stroma of pancreatic cancer [4,19,20]. The local structure of collagen organization is the result of complex physiological processes, which include the activity of collagen-producing and -remodeling cells [21,22] and physical factors such as interstitial flow, spatial movement, and expansion of proliferating cellular components [23,24].…”

Integrating computational pathology and proteomics to address tumor heterogeneity

“…Currently, molecular profiling efforts in clinical practice focus on characterizing and targeting the broad and overall genomic patterns of patients' cancer tissue through bulk tumor sampling approaches of only a single tumor region. In these common workflows, one tumor block is chosen to serve as a representative sample for molecular analyses and decision-making [2,12,13]. Despite the significant contributions these profiling approaches have made towards furthering the understanding of cancer biology and personalized clinical interventions, these profiling techniques often fail to translate into durable, life-prolonging cancer treatments [2,3,12,14].…”

“…In these common workflows, one tumor block is chosen to serve as a representative sample for molecular analyses and decision-making [2,12,13]. Despite the significant contributions these profiling approaches have made towards furthering the understanding of cancer biology and personalized clinical interventions, these profiling techniques often fail to translate into durable, life-prolonging cancer treatments [2,3,12,14]. A widely supported explanation for this phenomenon is the influence of diverse intratumoral subpopulations with differing therapeutic resistances, with multiple studies across cancer types implicating heterogeneous intratumoral biology in cancer treatment failure and poor patient outcomes (Figure 2) [2,12,13,15,16].…”

“…Despite the significant contributions these profiling approaches have made towards furthering the understanding of cancer biology and personalized clinical interventions, these profiling techniques often fail to translate into durable, life-prolonging cancer treatments [2,3,12,14]. A widely supported explanation for this phenomenon is the influence of diverse intratumoral subpopulations with differing therapeutic resistances, with multiple studies across cancer types implicating heterogeneous intratumoral biology in cancer treatment failure and poor patient outcomes (Figure 2) [2,12,13,15,16]. For example, in one study in which patients' glioblastomas were sampled across a number of spatially distinct regions, different mutations were found scattered throughout the sampled regions.…”

Perspective: The Mechanobiology of Hepatocellular Carcinoma

“…This has already been shown for pancreatic adenocarcinoma, where collagen and hyaluronic acid deposition correlate with large increases in interstitial fluid pressure and solid stress [ 27 , 29 , 30 ]. This phenomenon has primarily been examined in the context of drug delivery, as vessels within the tumor are constricted by increased pressure, preventing the penetration of chemotherapy drugs [ 31 , 32 , 33 ], however, more recently it has been shown that different stromal morphology in pancreatic cancer correlates to different functional outcomes, suggesting that matrix mechanical changes could alter oncogenesis and cancer progression [ 34 ]. Importantly, these mechanical changes do not act on cells in isolation ( Figure 1 ); increased interstitial pressure will compress the matrix, increasing the effective stiffness that cells sense in addition to directly compressing them.…”