Details

Autor(en) / Beteiligte

• Öhlund, Daniel
• Handly-Santana, Abram
• Elyada, Ela
• Biffi, Giulia
• Tuveson, David A.

Titel

Abstract B73: Pancreatic stellate cell heterogeneity in cancer

Ist Teil von

• Cancer research (Chicago, Ill.), 2016-12, Vol.76 (24_Supplement), p.B73-B73

Erscheinungsjahr

2016

Quelle

EZB Electronic Journals Library

Beschreibungen/Notizen

• Abstract Paracrine interactions between pancreatic stellate cells (PSCs) and tumor cells play key roles in pancreatic cancer tumorigenesis. However, attempts to therapeutically target the PSCs have implied that PSCs may also restrain tumor growth, raising the possibility of diverse and dynamic pathophysiological roles of these cells in cancer. In order to gain a deeper understanding of the functional heterogeneity found among PSCs, we have developed an organotypic co-culture system that allows the study of functional interactions between pancreatic tumor-derived organoids and PSCs in a three-dimensional basement membrane matrix (Matrigel). PSCs embedded in Matrigel acquire a quiescent phenotype and restore their vitamin A droplets similar to PSCs found in healthy pancreata in vivo. In co-culture the PSCs proliferate, form lattices around the organoids, and secrete extracellular matrix proteins and inflammatory cytokines. In turn, the organoids proliferate more rapidly in co-culture with PSCs compared to their mono-cultured counterparts, as well as survive passaging in reduced media conditions. Furthermore, we show that PSCs can differentiate into two distinct subtypes with different phenotypic features depending on the spatial proximity to the co-cultured organoids. PSCs found in direct contact with tumor cells express higher levels of smooth muscle actin (SMA), while PSCs that are more distant from the tumor cells show low SMA expression and gain a secretory phenotype. The secreted factors from this subtype of PSCs activate signaling pathways important for survival and proliferation in tumor organoids. We demonstrate that these two subtypes are mutually exclusive, and can both be found in vivo with similar spatial distribution as seen in the co-culture system. Taken together, we have identified two subtypes of PSCs present in pancreatic cancer with potentially different pathophysiological functions. Preferentially targeting one of these subtypes in future clinical trials may positively affect patient outcomes. Citation Format: Daniel Öhlund, Abram Handly-Santana, Ela Elyada, Giulia Biffi, David A. Tuveson.{Authors}. Pancreatic stellate cell heterogeneity in cancer. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr B73.