Developing drug combinations to co-target pancreatic cancer and its supporting stroma

Bioengineered tumoral microtissues recapitulate desmoplastic reaction of pancreatic cancer

“…Actually PDAC is characterized by a prominent desmoplastic reaction, which compresses the vascular bed thus reducing drug delivery and recruitment of immune competent cells that could represent important targets in this cancer type [60]. The desmoplastic reaction is driven by quiescent pancreatic stellate cells, which are activated by cancer cells to acquire a myofibroblasts (or CAF) phenotype, expressing some markers as α-SMA and PDGFβr [61]. In our 3D tumor model, native ECM is present and can carry out its regulatory role in guiding cell activation and tissue formation.…”

Arachidonate 15-lipoxygenase-mediated production of Resolvin D5n-3 DPA abrogates pancreatic stellate cell-induced cancer cell invasion

“…Using an organotypic model, PSCs are co-cultured and treated simultaneously with ATRA [to induce quiescence (6)] or PD146176 [an ALOX15 inhibitor (59), the initiating enzyme in RvD5 n-3 DPA biosynthesis (29)] as cells interact and invade into the gel. ATRA reproducibly reduces the number of invading cancer cells into the gel (Figures 4A-C) (6,7). In contrast, upon ALOX15 inhibition (PD146176) at the same time as ATRA treatment, this reduction in invasion is abrogated, supporting a potential role for RvD5 n-3 DPA in the observed activities of ATRA (Figure 1).…”

“…Healthy human, telomerase reverse transcriptase (hTERT) immortalized, pancreas-derived stellate cells (PS1) (37) and human primary CAFs (12) were grown as previously described. PS1s and CAFs were rendered quiescent by daily treatment with 1 µM all-trans retinoic acid (ATRA; R2625, Sigma-Aldrich) under subdued light conditions daily for 7 days or with contemporary vehicle (ethanol 0.01% v/v) controls (6,7). Two pancreatic cancer cell lines, AsPC-1 (CRL-1682, ATCC) and MIAPaCa-2 (CRL-1420, ATCC), based on their representation of PDAC diversity were employed (38).…”

“…Recently, stromal reprogramming (of PSCs) has met success in earlyphase clinical trials (5), opening an underexplored avenue to reverse the activated stroma to a homeostatic, physiological state along with chemotherapy to target pancreatic cancer cells. The precise mechanism(s) of the multitude of cross-talk has been restricted to protein signaling molecules such as Wnt-b-catenin (6), CXCL12 (4), RARb (7), PTX3 (8), CCL21, and CXCL13 (9) with scant attention being paid to lipid-derived signaling molecules.…”

Pancreatic stellate cells derived from human pancreatic cancer demonstrate aberrant SPARC-dependent ECM remodeling in 3D engineered fibrotic tissue of clinically relevant thickness

“…The shorter experimental duration may expedite mechanistic analyses or the screening for potential ECM-targeting drugs that normalize the abnormal ECM remodeling process in pancreatic cancer. Our 3D fibrotic model may be used as an alternative technique for in vitro analyses of tumor stroma in addition to previously established 3D organotypic models embedding PSCs within ECM gels [73][74][75], or 3D spheroidal models [8,32,76,77]. The advantage of our model is that it does not require different culture conditions to generate tissues of different thickness; the number of cells seeded is the only factor which needs to be tuned.…”